Topotecan

Identification

Summary

Topotecan is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical cancer.

Brand Names
Hycamtin
Generic Name
Topotecan
DrugBank Accession Number
DB01030
Background

An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerases, type I.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 421.4458
Monoisotopic: 421.163770861
Chemical Formula
C23H23N3O5
Synonyms
  • 9-[(dimethylamino)methyl]-10-hydroxy-(4S)-camptothecin
  • Topotecan
  • Topotecane
  • Topotecanum
External IDs
  • SK&F-104864
  • SKF-104864

Pharmacology

Indication

For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAcute myeloid leukemia••• •••••
Treatment ofRefractory neuroblastoma••• •••••
Treatment ofSarcoma, ewing's••• •••••
Treatment ofMetastatic rhabdomyosarcoma••• •••••
Used in combination to treatRecurrent, iv-b cervical cancerRegimen in combination with: Cisplatin (DB00515)•••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug.

Mechanism of action

Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death).

Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor.

TargetActionsOrganism
ADNA topoisomerase 1
inhibitor
Humans
ADNA
intercalation
Humans
UDNA topoisomerase I, mitochondrial
inhibitor
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

35%

Metabolism

Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active.

Route of elimination

Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%.

Half-life

2-3 hours

Clearance

Not Available

Adverse Effects
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Toxicity

The primary anticipated complication of overdosage would consist of bone marrow suppression.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

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.
DrugInteraction
AbacavirTopotecan may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbataceptThe risk or severity of adverse effects can be increased when Topotecan is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Topotecan.
AbemaciclibThe excretion of Abemaciclib can be decreased when combined with Topotecan.
AbrocitinibThe serum concentration of Topotecan can be increased when it is combined with Abrocitinib.
Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Topotecan hydrochloride956S425ZCY119413-54-6DGHHQBMTXTWTJV-BQAIUKQQSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
HycamtinCapsule1 mg/1OralNovartis Pharmaceuticals Corporation2017-02-24Not applicableUS flag
HycamtinCapsule0.25 mg/1OralGlaxoSmithKline Manufacturing SpA2008-09-162017-12-13US flag
HycamtinCapsule0.25 mgOralSandoz Pharmaceuticals D.D.2016-09-20Not applicableEU flag
HycamtinInjection, powder, for solution4 mgIntravenousSandoz Pharmaceuticals D.D.2016-09-20Not applicableEU flag
HycamtinCapsule1 mg/1OralGlaxosmithkline Inc2008-09-162018-01-31US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Mylan-topotecan Hydrochloride for InjectionPowder, for solution4 mg / vialIntravenousMylan PharmaceuticalsNot applicableNot applicableCanada flag
PMS-topotecanPowder, for solution4 mg / vialIntravenousPharmascience Inc2013-08-29Not applicableCanada flag
PMS-topotecanPowder, for solution1 mg / vialIntravenousPharmascience IncNot applicableNot applicableCanada flag
Teva-topotecanPowder, for solution1 mg / vialIntravenousTEVA Canada LimitedNot applicableNot applicableCanada flag
Teva-topotecanPowder, for solution4 mg / vialIntravenousTEVA Canada Limited2015-11-17Not applicableCanada flag

Categories

ATC Codes
L01CE01 — Topotecan
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as camptothecins. These are heterocyclic compounds comprising a planar pentacyclic ring structure, that includes a pyrrolo[3,4-beta]-quinoline moiety (rings A, B and C), conjugated pyridone moiety (ring D) and one chiral center at position 20 within the alpha-hydroxy lactone ring with (S) configuration (the E-ring).
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Camptothecins
Sub Class
Not Available
Direct Parent
Camptothecins
Alternative Parents
Hydroxyquinolines / Pyranopyridines / Pyridinones / 1-hydroxy-2-unsubstituted benzenoids / Aralkylamines / Tertiary alcohols / Heteroaromatic compounds / Trialkylamines / Amino acids and derivatives / Lactones
show 9 more
Substituents
1-hydroxy-2-unsubstituted benzenoid / Alcohol / Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Camptothecin / Carbonyl group
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
pyranoindolizinoquinoline (CHEBI:63632)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
7M7YKX2N15
CAS number
123948-87-8
InChI Key
UCFGDBYHRUNTLO-QHCPKHFHSA-N
InChI
InChI=1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1
IUPAC Name
(19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione
SMILES
CC[C@@]1(O)C(=O)OCC2=C1C=C1N(CC3=CC4=C(C=CC(O)=C4CN(C)C)N=C13)C2=O

References

Synthesis Reference

Venkata Raghavendra Palle, Sekhar Nariyam, Lankeshwara Matti, "PROCESS FOR PREPARING TOPOTECAN." U.S. Patent US20070149783, issued June 28, 2007.

US20070149783
General References
  1. Kollmannsberger C, Mross K, Jakob A, Kanz L, Bokemeyer C: Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12. [Article]
  2. Herben VM, ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996 Aug;31(2):85-102. [Article]
  3. Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ: An overview of the clinical pharmacology of topotecan. Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18. [Article]
Human Metabolome Database
HMDB0015164
KEGG Drug
D08618
KEGG Compound
C11158
PubChem Compound
60700
PubChem Substance
46505204
ChemSpider
54705
BindingDB
50008935
RxNav
57308
ChEBI
63632
ChEMBL
CHEMBL84
ZINC
ZINC000001611274
Therapeutic Targets Database
DAP000648
PharmGKB
PA451729
PDBe Ligand
TTC
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Topotecan
PDB Entries
1k4t / 1rr8 / 1rrj / 7nez / 7ojh / 7oji / 8bwq
FDA label
Download (78.6 KB)
MSDS
Download (29.3 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • GlaxoSmithKline Inc.
  • Pfizer Animal Health
Dosage Forms
FormRouteStrength
SolutionIntravenous4.346 mg
Powder
CapsuleOral.25 mg/1
CapsuleOral0.25 mg/1
CapsuleOral1 mg/1
CapsuleOral1 MG
Powder4 mg/1vial
CapsuleOral
Injection, powder, for solutionIntravenous4 mg
CapsuleOral0.25 mg
CapsuleOral1.00 mg
Injection, powder, for solutionIntravenous1 mg
InjectionIntravenous4 mg
Powder, for solutionIntravenous4 mg / vial
Powder, for solutionIntravenous1 mg / vial
Injection, powder, for solutionIntravenous; Parenteral1 MG
Injection, powder, for solutionIntravenous; Parenteral4 MG
Injection, powder, lyophilized, for solutionIntravenous4 mg
Injection, solution, concentrateIntravenous
InjectionIntravenous1 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous4 mg/15mL
Injection, solution, concentrateIntravenous1 mg/1mL
Injection, solution, concentrateIntravenous1 mg/ml
Injection, powder, for solutionIntravenous
Injection, solution, concentrateIntravenous; Parenteral1 MG/ML
Injection, powder, for solutionParenteral1 mg
Injection, powder, for solutionParenteral4 mg
Injection, solution, concentrateIntravenous; Parenteral4 MG/4ML
Injection, powder, for solutionIntravenous4 mg/4mL
Injection, powder, lyophilized, for solutionIntravenous4 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous4 mg/4mL
Injection, powder, for solution
SolutionIntravenous1 mg / mL
Injection, solution, concentrateIntravenous4 MG/4ML
Injection, solution, concentrateParenteral4 mg/4ml
Injection, powder, lyophilized, for solutionIntravenous
Injection, solutionIntravenous4 mg
SolutionParenteral4.000 mg
Prices
Unit descriptionCostUnit
Hycamtin 4 mg vial1306.1USD vial
Hycamtin 1 mg capsule358.92USD capsule
Hycamtin 0.25 mg capsule89.73USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5674872No1997-10-072015-04-07US flag
US5004758No1991-04-022010-05-28US flag
CA2103708No2004-04-272012-02-07Canada flag
CA2103707No2003-12-092012-02-07Canada flag
US8158645No2012-04-172024-12-10US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)213-218 °CNot Available
water solubility1 mg/mlNot Available
logP0.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.861 mg/mLALOGPS
logP1.84ALOGPS
logP-0.33Chemaxon
logS-2.7ALOGPS
pKa (Strongest Acidic)8Chemaxon
pKa (Strongest Basic)9.75Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area103.2 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity115.02 m3·mol-1Chemaxon
Polarizability44.86 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8911
Blood Brain Barrier-0.9659
Caco-2 permeable-0.6966
P-glycoprotein substrateSubstrate0.7918
P-glycoprotein inhibitor INon-inhibitor0.6121
P-glycoprotein inhibitor IINon-inhibitor0.9507
Renal organic cation transporterNon-inhibitor0.9
CYP450 2C9 substrateNon-substrate0.8844
CYP450 2D6 substrateNon-substrate0.8168
CYP450 3A4 substrateSubstrate0.6875
CYP450 1A2 substrateInhibitor0.5572
CYP450 2C9 inhibitorNon-inhibitor0.8305
CYP450 2D6 inhibitorNon-inhibitor0.8918
CYP450 2C19 inhibitorNon-inhibitor0.824
CYP450 3A4 inhibitorNon-inhibitor0.6464
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7184
Ames testNon AMES toxic0.6516
CarcinogenicityNon-carcinogens0.8504
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.0075 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9963
hERG inhibition (predictor II)Non-inhibitor0.8302
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-01rw-0019000000-dd5f6ac57d5951105684
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00b9-0019400000-11f24a2a9b88f6c67514
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-1001900000-759c1fd0f4c5abb7c8a9
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00b9-0009000000-6540b44d823ce30be40c
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0k92-3009300000-99ac09c2f262083e3a20
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-0009000000-2f00d69ed9f0bbf6e6c9
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-056r-3069100000-cda90fc80e56870747f4
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f72-0219100000-02094620b9cd7679e750
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-220.1395625
predicted
DarkChem Lite v0.1.0
[M-H]-193.78555
predicted
DeepCCS 1.0 (2019)
[M+H]+221.8336625
predicted
DarkChem Lite v0.1.0
[M+H]+196.18112
predicted
DeepCCS 1.0 (2019)
[M+Na]+221.1900625
predicted
DarkChem Lite v0.1.0
[M+Na]+202.09364
predicted
DeepCCS 1.0 (2019)

Targets

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Details
1. DNA topoisomerase 1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Poly(a) rna binding
Specific Function
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a singl...
Gene Name
TOP1
Uniprot ID
P11387
Uniprot Name
DNA topoisomerase 1
Molecular Weight
90725.19 Da
References
  1. Schmidt F, Rieger J, Wischhusen J, Naumann U, Weller M: Glioma cell sensitivity to topotecan: the role of p53 and topotecan-induced DNA damage. Eur J Pharmacol. 2001 Jan 19;412(1):21-5. [Article]
  2. strel'tsov SA, Mikheikin AL, Nechipurenko IuD: [Interaction of topotecan--a DNA topoisomerase I inhibitor--with dual-stranded polydeoxyribonucleotides. II. Formation of a complex containing several DNA molecules in the presence of topotecan]. Mol Biol (Mosk). 2001 May-Jun;35(3):442-50. [Article]
  3. Streltsov SA: Action models for the antitumor drug camptothecin: formation of alkali-labile complex with DNA and inhibition of human DNA topoisomerase I. J Biomol Struct Dyn. 2002 Dec;20(3):447-54. [Article]
  4. Zhang J, Pu SP, Zhou YJ: [Preliminary study of apoptosis of human hepatocarcinoma cell line HepG2 induced by topotecan]. Ai Zheng. 2002 Dec;21(12):1305-9. [Article]
  5. Aisner J, Musanti R, Beers S, Smith S, Locsin S, Rubin EH: Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance: a pharmacodynamically based Phase I trial. Clin Cancer Res. 2003 Jul;9(7):2504-9. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Kollmannsberger C, Mross K, Jakob A, Kanz L, Bokemeyer C: Topotecan - A novel topoisomerase I inhibitor: pharmacology and clinical experience. Oncology. 1999;56(1):1-12. [Article]
  8. Herben VM, ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet. 1996 Aug;31(2):85-102. [Article]
  9. Dennis MJ, Beijnen JH, Grochow LB, van Warmerdam LJ: An overview of the clinical pharmacology of topotecan. Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18. [Article]
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Intercalation
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L: The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. [Article]
  2. Pourquier P, Takebayashi Y, Urasaki Y, Gioffre C, Kohlhagen G, Pommier Y: Induction of topoisomerase I cleavage complexes by 1-beta -D-arabinofuranosylcytosine (ara-C) in vitro and in ara-C-treated cells. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1885-90. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Dna topoisomerase type ii (atp-hydrolyzing) activity
Specific Function
Releases the supercoiling and torsional tension of DNA introduced during duplication of mitochondrial DNA by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-str...
Gene Name
TOP1MT
Uniprot ID
Q969P6
Uniprot Name
DNA topoisomerase I, mitochondrial
Molecular Weight
69871.39 Da
References
  1. Kosovsky MJ, Soslau G: Immunological identification of human platelet mitochondrial DNA topoisomerase I. Biochim Biophys Acta. 1993 Jun 24;1164(1):101-7. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, Traxler P: Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 2004 Apr 1;64(7):2333-7. [Article]
  2. Maliepaard M, van Gastelen MA, Tohgo A, Hausheer FH, van Waardenburg RC, de Jong LA, Pluim D, Beijnen JH, Schellens JH: Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res. 2001 Apr;7(4):935-41. [Article]
  3. Sugimoto Y, Tsukahara S, Imai Y, Sugimoto Y, Ueda K, Tsuruo T: Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. Mol Cancer Ther. 2003 Jan;2(1):105-12. [Article]
  4. Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, Floot BG, Schellens JH: Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 1999 Sep 15;59(18):4559-63. [Article]
  5. Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, Schinkel AH: Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000 Oct 18;92(20):1651-6. [Article]
  6. Allen JD, Van Dort SC, Buitelaar M, van Tellingen O, Schinkel AH: Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res. 2003 Mar 15;63(6):1339-44. [Article]
  7. Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH: Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004 Aug 15;64(16):5804-11. [Article]
  8. Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF: Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res. 2010 Jun 1;70(11):4499-508. doi: 10.1158/0008-5472.CAN-09-4264. Epub 2010 May 11. [Article]
  9. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF: Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res. 2009 Jul 15;69(14):5885-92. doi: 10.1158/0008-5472.CAN-09-0700. Epub 2009 Jun 30. [Article]
  10. Rocchi E, Khodjakov A, Volk EL, Yang CH, Litman T, Bates SE, Schneider E: The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem Biophys Res Commun. 2000 Apr 29;271(1):42-6. [Article]
  11. Ishii M, Iwahana M, Mitsui I, Minami M, Imagawa S, Tohgo A, Ejima A: Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6. Anticancer Drugs. 2000 Jun;11(5):353-62. [Article]
  12. Yang CH, Schneider E, Kuo ML, Volk EL, Rocchi E, Chen YC: BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells. Biochem Pharmacol. 2000 Sep 15;60(6):831-7. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Collett A, Tanianis-Hughes J, Hallifax D, Warhurst G: Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo. Pharm Res. 2004 May;21(5):819-26. [Article]
  2. Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF: Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res. 2010 Jun 1;70(11):4499-508. doi: 10.1158/0008-5472.CAN-09-4264. Epub 2010 May 11. [Article]
  3. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF: Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res. 2009 Jul 15;69(14):5885-92. doi: 10.1158/0008-5472.CAN-09-0700. Epub 2009 Jun 30. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K: Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 Jul 15;74(2):359-71. doi: 10.1016/j.bcp.2007.04.010. Epub 2007 Apr 13. [Article]
  2. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [Article]
  3. Xu Y, Liu X, Wang Y, Zhou N, Peng J, Gong L, Ren J, Luo C, Luo X, Jiang H, Chen K, Zheng M: Combinatorial Pharmacophore Modeling of Multidrug and Toxin Extrusion Transporter 1 Inhibitors: a Theoretical Perspective for Understanding Multiple Inhibitory Mechanisms. Sci Rep. 2015 Sep 2;5:13684. doi: 10.1038/srep13684. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Data based on in vitro studies.
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K: Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 Jul 15;74(2):359-71. doi: 10.1016/j.bcp.2007.04.010. Epub 2007 Apr 13. [Article]
  2. Raj GM, Mathaiyan J, Wyawahare M, Rao KS, Priyadarshini R: Genetic polymorphisms of multidrug and toxin extrusion proteins (MATE1 and MATE2) in South Indian population. Bioimpacts. 2017;7(1):25-30. doi: 10.15171/bi.2017.04. Epub 2017 Feb 8. [Article]
  3. Drug-transporter interaction testing in drug discovery and development [Link]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48