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Identification
- Summary
Dabrafenib is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer.
- Brand Names
- Tafinlar
- Generic Name
- Dabrafenib
- DrugBank Accession Number
- DB08912
- Background
Dabrafenib mesylate (Tafinlar) is a reversible ATP-competitive kinase inhibitor and targets the MAPK pathway. It was approved on May 29, 2013, for the treatment of melanoma with V600E or V6000K mutation.20 It was also used for metastatic non-small cell lung cancer with the same mutation.20
In May 2018, Tafinlar (dabrafenib), in combination with Mekinist (Trametinib), was approved to treat anaplastic thyroid cancer caused by an abnormal BRAF V600E gene.20
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Dabrafenib (DB08912)
- Weight
- Average: 519.562
Monoisotopic: 519.101050904 - Chemical Formula
- C23H20F3N5O2S2
- Synonyms
- Dabrafenib
- External IDs
- GSK-2118436
- GSK-2118436A
- GSK2118436
- GSK2118436A
Pharmacology
- Indication
As monotherapy, dabrafenib is indicated to treat unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.20
In combination with trametinib, dabrafenib is indicated to treat for:
- the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.20
- the adjuvant treatment of melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection.20
- the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation.20
- the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options.20
- treatment of adult and pediatric patients six years and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).23
- the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.23
Dabrafenib has limitations of use: it is neither indicated for treating patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition nor wild-type BRAF solid tumours.23
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Low grade glioma (lgg) Regimen in combination with: Trametinib (DB08911) •••••••••••• ••••••• •••••••• ••••••• Used as adjunct in combination to treat Melanoma Regimen in combination with: Trametinib (DB08911) •••••••••••• ••••• •••• ••••••••••• Used as adjunct in combination to treat Melanoma Regimen in combination with: Trametinib (DB08911) •••••••••••• ••••• •••• ••••••••••• Used in combination to treat Metastatic anaplastic thyroid cancer Regimen in combination with: Trametinib (DB08911) •••••••••••• •••••••••• ••••••••••• ••••••••• ••••••• Used in combination to treat Metastatic melanoma Regimen in combination with: Trametinib (DB08911) •••••••••••• - Contraindications & Blackbox Warnings
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Dabrafenib is a kinase inhibitor that is mainly used to target BRAF V600E mutation in multiple types of cancer. Although dabrafenib and trametinib both inhibit the RAS/RAF/MEK/ERK pathway, they inhibit different effectors of the pathway, thus increasing response rate and mitigating resistance without cumulative toxicity.11
The melanoma approval for use with trametinib is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection. Patients received doses of dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met.16
In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.19
- Mechanism of action
Dabrafenib is a competitive and selective BRAF inhibitor by binding to its ATP pocket.20,5 Although dabrafenib can inhibit wild-type BRAF, it has a higher affinity for mutant forms of BRAF, including BRAF V600E, BRAF V600K, and BRAF V600D.20 BRAF is a serine/threonine protein kinase and is involved in activating the RAS/RAF/MEK/ERK or MAPK pathway, a pathway that is implicated in cell cycle progression, cell proliferation, and arresting apoptosis.6,7,8,9Therefore, constitutive active mutation of BRAF such as BRAF V600E is frequently observed in many types of cancer, including melanoma, lung cancer, and colon cancer.10
Target Actions Organism ASerine/threonine-protein kinase B-raf inhibitorHumans ARAF proto-oncogene serine/threonine-protein kinase inhibitorHumans USerine/threonine-protein kinase SIK1 inhibitorHumans USerine/threonine-protein kinase Nek11 inhibitorHumans ULIM domain kinase 1 inhibitorHumans - Absorption
After oral administration, the median time to achieve peak plasma concentration (Tmax) is 2 hours.20 Mean absolute bioavailability of oral dabrafenib is 95%.20 Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing.20 After repeated twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73, and the inter-subject variability (CV%) of AUC at steady-state was 38%.20
- Volume of distribution
The apparent volume of distribution (Vc/F) is 70.3 L.20Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein.2
- Protein binding
Dabrafenib is 99.7% bound to human plasma proteins.20
- Metabolism
The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites.20
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- Route of elimination
Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only.20
- Half-life
The mean terminal half-life of dabrafenib is 8 hours after oral administration. Hydroxy-dabrafenib's terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours).20
- Clearance
The clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice-daily dosing.20
- Adverse Effects
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Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials.20
Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay and was not clastogenic in an in vivo rat bone marrow micronucleus test.20
In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC).20
Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively.20
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
Interacting Gene/Enzyme Allele name Genotype(s) Defining Change(s) Type(s) Description Details Glucose-6-phosphate 1-dehydrogenase Villeurbanne Not Available 1000_1002delACC ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Torun Not Available 1006A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Sunderland Not Available 105_107delCAT ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Iwatsuki Not Available 1081G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Serres Not Available 1082C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Tondela Not Available 1084_1101delCTGAACGAGCGCAAGGCC ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Loma Linda Not Available 1089C->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Aachen Not Available 1089C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Tenri Not Available 1096A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Montpellier Not Available 1132G>A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Calvo Mackenna Not Available 1138A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Riley Not Available 1139T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Olomouc Not Available 1141T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Tomah Not Available 1153T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Lynwood Not Available 1154G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Madrid Not Available 1155C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Iowa, Walter Reed, Springfield Not Available 1156A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Beverly Hills, Genova, Iwate, Niigata, Yamaguchi Not Available 1160G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Hartford Not Available 1162A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Praha Not Available 1166A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Krakow Not Available 1175T>C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Wisconsin Not Available 1177C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Nashville, Anaheim, Portici Not Available 1178G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Alhambra Not Available 1180G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Bari Not Available 1187C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Puerto Limon Not Available 1192G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Covao do Lobo Not Available 1205C>A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Clinic Not Available 1215G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Utrecht Not Available 1225C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Suwalki Not Available 1226C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Riverside Not Available 1228G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Japan, Shinagawa Not Available 1229G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Kawasaki Not Available 1229G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Munich Not Available 1231A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Georgia Not Available 1284C->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Sumare Not Available 1292T->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Telti/Kobe Not Available 1318C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Santiago de Cuba, Morioka Not Available 1339G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Harima Not Available 1358T->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Figuera da Foz Not Available 1366G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Amiens Not Available 1367A>T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Bangkok Noi Not Available 1376G->T, 1502T->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Fukaya Not Available 1462G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Campinas Not Available 1463G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Buenos Aires Not Available 1465C>T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Arakawa Not Available 1466C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Brighton Not Available 1488_1490delGAA ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Kozukata Not Available 159G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Amsterdam Not Available 180_182delTCT ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase No name Not Available 202G->A, 376A->G, 1264C>G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Swansea Not Available 224T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Urayasu Not Available 281_283delAGA ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Vancouver Not Available 317C->G544C->T592C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Mt Sinai Not Available 376A->G, 1159C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Plymouth Not Available 488G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Volendam Not Available 514C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Shinshu Not Available 527A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Chikugo Not Available 535A->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Tsukui Not Available 561_563delCTC ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Pedoplis-Ckaro Not Available 573C>G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Santiago Not Available 593G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Minnesota, Marion, Gastonia, LeJeune Not Available 637G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Cincinnati Not Available 637G->T, 1037A->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Harilaou Not Available 648T->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase North Dallas Not Available 683_685delACA ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Asahikawa Not Available 695G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Durham Not Available 713A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Stonybrook Not Available 724_729delGGCACT ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Wayne Not Available 769C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Aveiro Not Available 806G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Cleveland Corum Not Available 820G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Lille Not Available 821A>T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Bangkok Not Available 825G>C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Sugao Not Available 826C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase La Jolla Not Available 832T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Wexham Not Available 833C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Piotrkow Not Available 851T>C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase West Virginia Not Available 910G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Omiya Not Available 921G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Nara Not Available 953_976delCCACCAAAGGGTACCTGGAC GACC ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Manhattan Not Available 962G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Rehevot Not Available 964T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Honiara Not Available 99A->G / 1360C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Tokyo, Fukushima Not Available 1246G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Chatham Not Available 1003G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Fushan Not Available 1004C->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Partenope Not Available 1052G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Ierapetra Not Available 1057C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Anadia Not Available 1193A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Abeno Not Available 1220A->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Surabaya Not Available 1291G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Pawnee Not Available 1316G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase S. Antioco Not Available 1342A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Cassano Not Available 1347G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Hermoupolis Not Available 1347G->C / 1360C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Union,Maewo, Chinese-2, Kalo Not Available 1360C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Andalus Not Available 1361G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Cosenza Not Available 1376G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Canton, Taiwan- Hakka, Gifu-like, Agrigento-like Not Available 1376G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Flores Not Available 1387C->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Kaiping, Anant, Dhon, Sapporo-like, Wosera Not Available 1388G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Kamogawa Not Available 169C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Costanzo Not Available 179T>C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Amazonia Not Available 185C->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Songklanagarind Not Available 196T->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Hechi Not Available 202G->A / 871G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Namouru Not Available 208T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Bao Loc Not Available 352T>C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Crispim Not Available 375G->T, 379G->T383T->C384C>T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Acrokorinthos Not Available 376A->G / 463C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Santa Maria Not Available 376A->G / 542A->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Ananindeua Not Available 376A->G / 871G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Vanua Lava Not Available 383T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Valladolid Not Available 406C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Belem Not Available 409C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Liuzhou Not Available 442G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Shenzen Not Available 473G>A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Taipei ‚ÄúChinese- 3‚Äù Not Available 493A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Toledo Not Available 496C>T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Naone Not Available 497G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Nankang Not Available 517T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Miaoli Not Available 519C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Mediterranean, Dallas, Panama‚ Sassari, Cagliari, Birmingham Not Available 563C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Coimbra Shunde Not Available 592C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Nilgiri Not Available 593G>A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Radlowo Not Available 679C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Roubaix Not Available 811G>C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Haikou Not Available 835A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Chinese-1 Not Available 835A->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Mizushima Not Available 848A>G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Osaka Not Available 853C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Viangchan, Jammu Not Available 871G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Seoul Not Available 916G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Ludhiana Not Available 929G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Farroupilha Not Available 977C->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Chinese-5 Not Available 1024C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Rignano Not Available 130G>A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Orissa Not Available 131C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase G6PDNice Not Available 1380G>C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Kamiube, Keelung Not Available 1387C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Neapolis Not Available 1400C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Aures Not Available 143T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Split Not Available 1442C->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Kambos Not Available 148C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Palestrina Not Available 170G>A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Metaponto Not Available 172G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Musashino Not Available 185C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Asahi Not Available 202G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase A- (202), Ferrara I Not Available 202G->A / 376A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Murcia Oristano Not Available 209A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Ube Konan Not Available 241C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Lagosanto Not Available 242G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Guangzhou Not Available 274C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Hammersmith Not Available 323T->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Sinnai Not Available 34G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase A- (680) Not Available 376A->G / 680G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase A- (968), Betica,Selma, Guantanamo Not Available 376A->G / 968T->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Salerno Pyrgos Not Available 383T>G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Quing Yan Not Available 392G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Lages Not Available 40G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Ilesha Not Available 466G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Mahidol Not Available 487G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Malaga Not Available 542A->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Sibari Not Available 634A->G ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Mexico City Not Available 680G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Nanning Not Available 703C->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Seattle, Lodi, Modena, Ferrara II, Athens-like Not Available 844G->C ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Bajo Maumere Not Available 844G->T ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Montalbano Not Available 854G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Kalyan-Kerala, Jamnaga, Rohini Not Available 949G->A ADR Inferred Increased risk of hemolytic anemia. Details Glucose-6-phosphate 1-dehydrogenase Gaohe Not Available 95A->G ADR Inferred Increased risk of hemolytic anemia. Details
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The serum concentration of 1,2-Benzodiazepine can be decreased when it is combined with Dabrafenib. Abacavir The metabolism of Abacavir can be decreased when combined with Dabrafenib. Abametapir The serum concentration of Dabrafenib can be increased when it is combined with Abametapir. Abatacept The metabolism of Dabrafenib can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be decreased when it is combined with Dabrafenib. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of dabrafenib.
- Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of dabrafenib.
- Do not take with or immediately after a high-fat meal. Dabrafenib's bioavailability is reduced when taken with a high-fat meal.
- Take on an empty stomach. Take dabrafenib at least one hour before or two hours after a meal.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Dabrafenib mesylate B6DC89I63E 1195768-06-9 YKGMKSIHIVVYKY-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Finlee Tablet, for suspension 10 mg Oral Novartis Europharm Limited 2024-07-10 Not applicable EU 
Finlee Tablet, for suspension 10 mg Oral Novartis Europharm Limited 2024-07-10 Not applicable EU Tafinlar Capsule 75 mg/1 Oral Glaxosmithkline Inc 2013-06-10 2018-05-31 US 
Tafinlar Capsule 75 mg Oral Novartis Europharm Limited 2021-03-17 Not applicable EU Tafinlar Capsule 50 mg Oral Novartis Europharm Limited 2021-03-17 Not applicable EU
Categories
- ATC Codes
- L01EC02 — Dabrafenib
- Drug Categories
- Amines
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- B-Raf serine-threonine kinase (BRAF) inhibitors
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP1A2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (strength unknown)
- Cytochrome P-450 CYP2B6 Inhibitors
- Cytochrome P-450 CYP2B6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C19 Inducers (strength unknown)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C19 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C8 Inducers (weak)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (strong)
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C8 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2C9 Inducers
- Cytochrome P-450 CYP2C9 Inducers (strength unknown)
- Cytochrome P-450 CYP2C9 Inducers (strong)
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2C9 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Drugs causing inadvertant photosensitivity
- Enzyme Inhibitors
- Hydroxylamines
- Hyperglycemia-Associated Agents
- Kinase Inhibitor
- Narrow Therapeutic Index Drugs
- OAT1/SLC22A6 inhibitors
- OAT3/SLC22A8 Inhibitors
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B1/SLCO1B1 Substrates
- OATP1B3 inhibitors
- OATP1B3 substrates
- OCT2 Inhibitors
- Organic Anion Transporter 1 Inhibitors
- Organic Anion Transporting Polypeptide 1B1 Inhibitors
- Organic Anion Transporting Polypeptide 1B3 Inhibitors
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Photosensitizing Agents
- Potential QTc-Prolonging Agents
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins B-raf, antagonists & inhibitors
- QTc Prolonging Agents
- UGT1A1 Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as sulfanilides. These are organic aromatic compounds containing a sulfanilide moiety, with the general structure RS(=O)(=O)NC1=CC=CC=C1.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Sulfanilides
- Direct Parent
- Sulfanilides
- Alternative Parents
- Benzenesulfonamides / Benzenesulfonyl compounds / 2,4,5-trisubstituted thiazoles / Fluorobenzenes / Aminopyrimidines and derivatives / Organosulfonamides / Aryl fluorides / Heteroaromatic compounds / Aminosulfonyl compounds / Azacyclic compounds show 5 more
- Substituents
- 2,4,5-trisubstituted 1,3-thiazole / Amine / Aminopyrimidine / Aminosulfonyl compound / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenesulfonamide show 22 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- organofluorine compound, aminopyrimidine, sulfonamide, 1,3-thiazole (CHEBI:75045)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- QGP4HA4G1B
- CAS number
- 1195765-45-7
- InChI Key
- BFSMGDJOXZAERB-UHFFFAOYSA-N
- InChI
- InChI=1S/C23H20F3N5O2S2/c1-23(2,3)21-30-18(19(34-21)16-10-11-28-22(27)29-16)12-6-4-9-15(17(12)26)31-35(32,33)20-13(24)7-5-8-14(20)25/h4-11,31H,1-3H3,(H2,27,28,29)
- IUPAC Name
- N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene-1-sulfonamide
- SMILES
- CC(C)(C)C1=NC(=C(S1)C1=NC(N)=NC=C1)C1=C(F)C(NS(=O)(=O)C2=C(F)C=CC=C2F)=CC=C1
References
- General References
- Gibney GT, Zager JS: Clinical development of dabrafenib in BRAF mutant melanoma and other malignancies. Expert Opin Drug Metab Toxicol. 2013 Jul;9(7):893-9. doi: 10.1517/17425255.2013.794220. Epub 2013 Apr 29. [Article]
- Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF: Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013 Mar;344(3):655-64. doi: 10.1124/jpet.112.201475. Epub 2012 Dec 17. [Article]
- Suo Z, Xiong X, Sun Q, Zhao L, Tang P, Hou Q, Zhang Y, Wu D, Li H: Investigation on the Interaction of Dabrafenib with Human Serum Albumin Using Combined Experiment and Molecular Dynamics Simulation: Exploring the Binding Mechanism, Esterase-like Activity, and Antioxidant Activity. Mol Pharm. 2018 Dec 3;15(12):5637-5645. doi: 10.1021/acs.molpharmaceut.8b00806. Epub 2018 Nov 20. [Article]
- Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16. [Article]
- Millet A, Martin AR, Ronco C, Rocchi S, Benhida R: Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges. Med Res Rev. 2017 Jan;37(1):98-148. doi: 10.1002/med.21404. Epub 2016 Aug 29. [Article]
- Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, Palmieri G, Testori A, Marincola FM, Mozzillo N: The role of BRAF V600 mutation in melanoma. J Transl Med. 2012 Jul 9;10:85. doi: 10.1186/1479-5876-10-85. [Article]
- Sullivan RJ, Flaherty KT: BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance. J Skin Cancer. 2011;2011:423239. doi: 10.1155/2011/423239. Epub 2011 Nov 17. [Article]
- McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. doi: 10.1016/j.bbamcr.2006.10.001. Epub 2006 Oct 7. [Article]
- Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR: Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol. 2003 Jul;5(7):647-54. [Article]
- Holderfield M, Deuker MM, McCormick F, McMahon M: Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer. 2014 Jul;14(7):455-67. doi: 10.1038/nrc3760. [Article]
- Brugnara S, Sicher M, Bonandini EM, Donner D, Chierichetti F, Barbareschi M, Girardelli CR, Caffo O: Treatment with combined dabrafenib and trametinib in BRAF(V600E)-mutated metastatic malignant melanoma: a case of long-term complete response after treatment cessation. Drugs Context. 2018 Feb 15;7:212515. doi: 10.7573/dic.212515. eCollection 2018. [Article]
- Ellens H, Johnson M, Lawrence SK, Watson C, Chen L, Richards-Peterson LE: Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites. Drug Metab Dispos. 2017 Jun;45(6):646-656. doi: 10.1124/dmd.116.073932. Epub 2017 Mar 20. [Article]
- Dabrafenib [Link]
- Drug Duo, Tafinlar and Mekinist, Approved for Aggressive Thyroid Cancer [Link]
- FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation [Link]
- Novartis receives FDA approval of Tafinlar® + Mekinist® for adjuvant treatment of BRAF V600-mutant melanoma [Link]
- Dabrafenib [Link]
- Cancer. gov Dabrafenib [Link]
- Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer [Link]
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Santa Cruz Biotech: Dabrafenib MSDS [Link]
- GSK: Dabrafenib MSDS [Link]
- FDA Approved Drug Products: TAFINLAR (dabrafenib) Oral Capsules or Tablets for Oral Suspension (March 2023) [Link]
- FDA Approved Drug Products: TAFINLAR (dabrafenib) Oral Capsules or Tablets for Oral Suspension (June 2023) [Link]
- NZ DrugSafe Tafinlar [File]
- Monograph, Tafinlar [File]
- External Links
- Human Metabolome Database
- HMDB0250818
- KEGG Drug
- D10064
- PubChem Compound
- 44462760
- PubChem Substance
- 175427150
- ChemSpider
- 25948204
- BindingDB
- 50428286
- 1424911
- ChEBI
- 75045
- ChEMBL
- CHEMBL2028663
- ZINC
- ZINC000068153186
- PDBe Ligand
- P06
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Dabrafenib
- PDB Entries
- 4xv2 / 5csw / 5hie / 6hj2 / 6v2u / 7riv
- FDA label
- Download (418 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Available Not Available Adjuvant / Melanoma 1 somestatus stop reason just information to hide Not Available Available Not Available Melanoma 1 somestatus stop reason just information to hide Not Available Available Not Available Small Cell Lung Cancer (SCLC) 1 somestatus stop reason just information to hide Not Available Completed Not Available Malignant Melanoma 1 somestatus stop reason just information to hide Not Available Completed Not Available Malignant Melanoma Stage IIIc / Stage IV Malignant Melanoma 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 50 mg/1 Capsule Oral 75 mg/1 Tablet, for suspension Oral 10 mg Tablet, for suspension Oral 10 mg/1 Capsule Oral 50 mg Capsule Oral 75 mg Capsule, coated Oral 50 mg Capsule, coated Oral 75 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7994185 Yes 2011-08-09 2030-07-20 US US8415345 Yes 2013-04-09 2030-07-20 US US9233956 Yes 2016-01-12 2029-11-04 US US8703781 Yes 2014-04-22 2031-04-15 US US8835443 Yes 2014-09-16 2025-12-10 US US8952018 Yes 2015-02-10 2031-04-15 US US10869869 Yes 2020-12-22 2034-03-02 US US11504333 Yes 2018-12-29 2038-12-29 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source boiling point (°C) 653.7 https://datasheets.scbt.com/sds/aghs/en/sc-364477.pdf water solubility very slightly soluble at pH 1 http://www.medsafe.govt.nz/profs/Datasheet/t/tafinlarcap.pdf logP 2.9 http://www.medsafe.govt.nz/profs/Datasheet/t/tafinlarcap.pdf pKa -1.5 http://www.medsafe.govt.nz/profs/Datasheet/t/tafinlarcap.pdf - Predicted Properties
Property Value Source Water Solubility 0.00327 mg/mL ALOGPS logP 5.44 ALOGPS logP 5.46 Chemaxon logS -5.2 ALOGPS pKa (Strongest Acidic) 7.16 Chemaxon pKa (Strongest Basic) 2.97 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 110.86 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 127.51 m3·mol-1 Chemaxon Polarizability 49.71 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9944 Blood Brain Barrier + 0.7232 Caco-2 permeable + 0.5069 P-glycoprotein substrate Non-substrate 0.7965 P-glycoprotein inhibitor I Non-inhibitor 0.6468 P-glycoprotein inhibitor II Non-inhibitor 0.7039 Renal organic cation transporter Non-inhibitor 0.8694 CYP450 2C9 substrate Non-substrate 0.8233 CYP450 2D6 substrate Non-substrate 0.7346 CYP450 3A4 substrate Non-substrate 0.5834 CYP450 1A2 substrate Inhibitor 0.5219 CYP450 2C9 inhibitor Inhibitor 0.5 CYP450 2D6 inhibitor Non-inhibitor 0.8459 CYP450 2C19 inhibitor Non-inhibitor 0.5 CYP450 3A4 inhibitor Inhibitor 0.7531 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8612 Ames test Non AMES toxic 0.7078 Carcinogenicity Non-carcinogens 0.8093 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.4329 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9848 hERG inhibition (predictor II) Non-inhibitor 0.7704
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 205.10555 predictedDeepCCS 1.0 (2019) [M+H]+ 207.5011 predictedDeepCCS 1.0 (2019) [M+Na]+ 213.74089 predictedDeepCCS 1.0 (2019)
Targets
Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Although dabrafenib can target the wild-type BRAF, it is mostly used to inhibit mutated forms of BRAF, such as BRAF V600E, BRAF V600K, and BRAF V600D.[L41955]
- General Function
- Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role in the postsynaptic responses of hippocampal neurons (PubMed:1508179)
- Specific Function
- ATP binding
- Gene Name
- BRAF
- Uniprot ID
- P15056
- Uniprot Name
- Serine/threonine-protein kinase B-raf
- Molecular Weight
- 84436.135 Da
References
- Gibney GT, Zager JS: Clinical development of dabrafenib in BRAF mutant melanoma and other malignancies. Expert Opin Drug Metab Toxicol. 2013 Jul;9(7):893-9. doi: 10.1517/17425255.2013.794220. Epub 2013 Apr 29. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation
- Specific Function
- ATP binding
- Gene Name
- RAF1
- Uniprot ID
- P04049
- Uniprot Name
- RAF proto-oncogene serine/threonine-protein kinase
- Molecular Weight
- 73051.025 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, CRTC1/TORC1. Inhibits CREB activity by phosphorylating and inhibiting activity of TORCs, the CREB-specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signaling (PubMed:29211348). Acts as a tumor suppressor and plays a key role in p53/TP53-dependent anoikis, a type of apoptosis triggered by cell detachment: required for phosphorylation of p53/TP53 in response to loss of adhesion and is able to suppress metastasis. Part of a sodium-sensing signaling network, probably by mediating phosphorylation of PPME1: following increases in intracellular sodium, SIK1 is activated by CaMK1 and phosphorylates PPME1 subunit of protein phosphatase 2A (PP2A), leading to dephosphorylation of sodium/potassium-transporting ATPase ATP1A1 and subsequent increase activity of ATP1A1. Acts as a regulator of muscle cells by phosphorylating and inhibiting class II histone deacetylases HDAC4 and HDAC5, leading to promote expression of MEF2 target genes in myocytes. Also required during cardiomyogenesis by regulating the exit of cardiomyoblasts from the cell cycle via down-regulation of CDKN1C/p57Kip2. Acts as a regulator of hepatic gluconeogenesis by phosphorylating and repressing the CREB-specific coactivators CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB activity. Also regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. In concert with CRTC1/TORC1, regulates the light-induced entrainment of the circadian clock by attenuating PER1 induction; represses CREB-mediated transcription of PER1 by phosphorylating and deactivating CRTC1/TORC1 (By similarity)
- Specific Function
- 14-3-3 protein binding
- Gene Name
- SIK1
- Uniprot ID
- P57059
- Uniprot Name
- Serine/threonine-protein kinase SIK1
- Molecular Weight
- 84901.25 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Protein kinase which plays an important role in the G2/M checkpoint response to DNA damage. Controls degradation of CDC25A by directly phosphorylating it on residues whose phosphorylation is required for BTRC-mediated polyubiquitination and degradation
- Specific Function
- ATP binding
- Gene Name
- NEK11
- Uniprot ID
- Q8NG66
- Uniprot Name
- Serine/threonine-protein kinase Nek11
- Molecular Weight
- 74191.62 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways (PubMed:10436159, PubMed:11832213, PubMed:12807904, PubMed:15660133, PubMed:16230460, PubMed:18028908, PubMed:22328514, PubMed:23633677). Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop (PubMed:10436159). LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton (PubMed:11832213, PubMed:15660133, PubMed:16230460, PubMed:23633677). In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation (PubMed:11832213, PubMed:15660133, PubMed:16230460, PubMed:23633677). Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly (PubMed:18028908). Stimulates axonal outgrowth and may be involved in brain development (PubMed:18028908)
- Specific Function
- ATP binding
- Gene Name
- LIMK1
- Uniprot ID
- P53667
- Uniprot Name
- LIM domain kinase 1
- Molecular Weight
- 72584.4 Da
References
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitorInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Rowland A, van Dyk M, Hopkins AM, Mounzer R, Polasek TM, Rostami-Hodjegan A, Sorich MJ: Physiologically Based Pharmacokinetic Modeling to Identify Physiological and Molecular Characteristics Driving Variability in Drug Exposure. Clin Pharmacol Ther. 2018 Dec;104(6):1219-1228. doi: 10.1002/cpt.1076. Epub 2018 Apr 19. [Article]
- Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]
- Creusot N, Gassiot M, Alaterre E, Chiavarina B, Grimaldi M, Boulahtouf A, Toporova L, Gerbal-Chaloin S, Daujat-Chavanieu M, Matheux A, Rahmani R, Gongora C, Evrard A, Pourquier P, Balaguer P: The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor. Cells. 2020 Jul 8;9(7). pii: cells9071641. doi: 10.3390/cells9071641. [Article]
- Flockhart Table of Drug Interactions [Link]
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [Article]
- Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]
- Creusot N, Gassiot M, Alaterre E, Chiavarina B, Grimaldi M, Boulahtouf A, Toporova L, Gerbal-Chaloin S, Daujat-Chavanieu M, Matheux A, Rahmani R, Gongora C, Evrard A, Pourquier P, Balaguer P: The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor. Cells. 2020 Jul 8;9(7). pii: cells9071641. doi: 10.3390/cells9071641. [Article]
- Flockhart Table of Drug Interactions [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- InhibitorInducer
- Curator comments
- Only desmethyl-dabrafenib, a metabolite of dabrafenib, showed inhibition of CYP2B6.[A38175]
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]
- Flockhart Table of Drug Interactions [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitorInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Suttle AB, Grossmann KF, Ouellet D, Richards-Peterson LE, Aktan G, Gordon MS, LoRusso PM, Infante JR, Sharma S, Kendra K, Patel M, Pant S, Arkenau HT, Middleton MR, Blackman SC, Botbyl J, Carson SW: Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. J Clin Pharmacol. 2015 Apr;55(4):392-400. doi: 10.1002/jcph.437. Epub 2014 Dec 30. [Article]
- Brody T. (2018). FDA's Drugreview Process and the Package Label. Academic Press.
- EMA Label: Tafinlar (dabrafenib mesilate) Summary of Product Characteristics [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitorInducer
- Curator comments
- CYP2C19 has a minor contribution to the metabolism of desmethyl-dabrafenib only.[A38175]
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]
- Creusot N, Gassiot M, Alaterre E, Chiavarina B, Grimaldi M, Boulahtouf A, Toporova L, Gerbal-Chaloin S, Daujat-Chavanieu M, Matheux A, Rahmani R, Gongora C, Evrard A, Pourquier P, Balaguer P: The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor. Cells. 2020 Jul 8;9(7). pii: cells9071641. doi: 10.3390/cells9071641. [Article]
- EMA Label: Tafinlar (dabrafenib mesilate) Summary of Product Characteristics [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- Only hydroxyl-dabrafenib, a metabolite of dabrafenib, showed inhibition of CYP2B6.[A38175]
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk. Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1A1
- Molecular Weight
- 59590.91 Da
References
- Wang Z, Wang X, Wang Z, Fan X, Yan M, Jiang L, Xia Y, Cao J, Liu Y: Prediction of Drug-Drug Interaction Between Dabrafenib and Irinotecan via UGT1A1-Mediated Glucuronidation. Eur J Drug Metab Pharmacokinet. 2022 May;47(3):353-361. doi: 10.1007/s13318-021-00740-x. Epub 2022 Feb 11. [Article]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- Suo Z, Xiong X, Sun Q, Zhao L, Tang P, Hou Q, Zhang Y, Wu D, Li H: Investigation on the Interaction of Dabrafenib with Human Serum Albumin Using Combined Experiment and Molecular Dynamics Simulation: Exploring the Binding Mechanism, Esterase-like Activity, and Antioxidant Activity. Mol Pharm. 2018 Dec 3;15(12):5637-5645. doi: 10.1021/acs.molpharmaceut.8b00806. Epub 2018 Nov 20. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF: Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013 Mar;344(3):655-64. doi: 10.1124/jpet.112.201475. Epub 2012 Dec 17. [Article]
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF: Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013 Mar;344(3):655-64. doi: 10.1124/jpet.112.201475. Epub 2012 Dec 17. [Article]
- Ellens H, Johnson M, Lawrence SK, Watson C, Chen L, Richards-Peterson LE: Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites. Drug Metab Dispos. 2017 Jun;45(6):646-656. doi: 10.1124/dmd.116.073932. Epub 2017 Mar 20. [Article]
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- Curator comments
- Only carboxy-dabrafenib, a metabolite of dabrafenib, showed transportation through the OAT1B1 transporter.[A248940]
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- Ellens H, Johnson M, Lawrence SK, Watson C, Chen L, Richards-Peterson LE: Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites. Drug Metab Dispos. 2017 Jun;45(6):646-656. doi: 10.1124/dmd.116.073932. Epub 2017 Mar 20. [Article]
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- Curator comments
- Only carboxy-dabrafenib, a metabolite of dabrafenib, showed transportation through the OAT1B3 transporter.[A248940]
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- Ellens H, Johnson M, Lawrence SK, Watson C, Chen L, Richards-Peterson LE: Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites. Drug Metab Dispos. 2017 Jun;45(6):646-656. doi: 10.1124/dmd.116.073932. Epub 2017 Mar 20. [Article]
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- Curator comments
- Only carboxy-dabrafenib, a metabolite of dabrafenib, showed transportation through the OAT1A2 transporter.[A248940]
- General Function
- Na(+)-independent transporter that mediates the cellular uptake of a broad range of organic anions such as the endogenous bile salts cholate and deoxycholate, either in their unconjugated or conjugated forms (taurocholate and glycocholate), at the plasmam membrane (PubMed:19129463, PubMed:7557095). Responsible for intestinal absorption of bile acids (By similarity). Transports dehydroepiandrosterone 3-sulfate (DHEAS), a major circulating steroid secreted by the adrenal cortex, as well as estrone 3-sulfate and 17beta-estradiol 17-O-(beta-D-glucuronate) (PubMed:11159893, PubMed:12568656, PubMed:19129463, PubMed:23918469, PubMed:25560245, PubMed:9539145). Mediates apical uptake of all-trans-retinol (atROL) across human retinal pigment epithelium, which is essential to maintaining the integrity of the visual cycle and thus vision (PubMed:25560245). Involved in the uptake of clinically used drugs (PubMed:17301733, PubMed:20686826, PubMed:27777271). Capable of thyroid hormone transport (both T3 or 3,3',5'-triiodo-L-thyronine, and T4 or L-tyroxine) (PubMed:19129463, PubMed:20358049). Also transports prostaglandin E2 (PubMed:19129463). Plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells (By similarity). May also play a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1A2
- Uniprot ID
- P46721
- Uniprot Name
- Solute carrier organic anion transporter family member 1A2
- Molecular Weight
- 74144.105 Da
References
- Ellens H, Johnson M, Lawrence SK, Watson C, Chen L, Richards-Peterson LE: Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites. Drug Metab Dispos. 2017 Jun;45(6):646-656. doi: 10.1124/dmd.116.073932. Epub 2017 Mar 20. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651)
- Specific Function
- alpha-ketoglutarate transmembrane transporter activity
- Gene Name
- SLC22A6
- Uniprot ID
- Q4U2R8
- Uniprot Name
- Solute carrier family 22 member 6
- Molecular Weight
- 61815.78 Da
References
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:14586168, PubMed:15644426, PubMed:15846473, PubMed:16455804, PubMed:31553721). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:14586168, PubMed:15846473, PubMed:15864504, PubMed:22108572, PubMed:23832370). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:11306713, PubMed:14586168, PubMed:15846473). E1S transport is pH- and chloride-dependent and may also involve E1S/cGMP exchange (PubMed:26377792). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule (PubMed:11907186). Involved in the transport of neuroactive tryptophan metabolites kynurenate and xanthurenate (PubMed:22108572, PubMed:23832370). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (PubMed:15644426). May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate (PubMed:11669456, PubMed:15846473, PubMed:16455804). Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS), indole acetate (IA), hippurate/N-benzoylglycine (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor) (PubMed:14675047). May contribute to the release of cortisol in the adrenals (PubMed:15864504). Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile (By similarity). Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU) (By similarity). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (By similarity)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Organic anion transporter 3
- Molecular Weight
- 59855.585 Da
References
- FDA Approved Drug Proucts: TAFINLAR® (dabrafenib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:9260930, PubMed:9687576). Functions as a Na(+)-independent, bidirectional uniporter (PubMed:21128598, PubMed:9687576). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:15212162, PubMed:9260930, PubMed:9687576). However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached (By similarity). Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (PubMed:15783073). Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters (PubMed:16581093, PubMed:17460754, PubMed:9687576). Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system (PubMed:17460754). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN) (PubMed:12089365, PubMed:15212162, PubMed:17072098, PubMed:24961373, PubMed:9260930). Mediates the uptake and efflux of quaternary ammonium compound choline (PubMed:9260930). Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine (PubMed:12538837, PubMed:21128598). Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:12395288, PubMed:16394027). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- acetylcholine transmembrane transporter activity
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- Ellens H, Johnson M, Lawrence SK, Watson C, Chen L, Richards-Peterson LE: Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites. Drug Metab Dispos. 2017 Jun;45(6):646-656. doi: 10.1124/dmd.116.073932. Epub 2017 Mar 20. [Article]
Drug created at June 24, 2013 21:54 / Updated at August 02, 2024 07:31