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Identification
- Summary
Sparsentan is an endothelin and angiotensin II receptor antagonist indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression.
- Brand Names
- Filspari
- Generic Name
- Sparsentan
- DrugBank Accession Number
- DB12548
- Background
Sparsentan is a dual antagonist of the endothelin type A receptor (ETAR) and the angiotensin II (Ang II) type 1 receptor (AT1R) with a similar affinity for both (9.3 nM for ETAR and 0.8 nM for AT1R).2,5 Sparsentan is first in its class and orally active, and was created by merging the structural elements of irbesartan, an AT1R antagonist, and biphenylsulfonamide, an ETAR antagonist.2
In February 2023, the use of sparsentan to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression was approved by the FDA under accelerated approval based on reduction of proteinuria.5,7 In September 2024, it was granted full approval for an expanded indication.9 Sparsentan was initially developed for the treatment of hypertension;4 however, it has shown to be efficient in the reduction of proteinuria in patients with IgAN and focal segmental glomerulosclerosis (FSGS).1,3,6 Compared to irbesartan, sparsentan reduces proteinuria to a greater extent. Furthermore, it is the first non-immunosuppressive therapy for the reduction of proteinuria in IgAN.7 The use of sparsentan may cause hepatotoxicity and embryo-fetal toxicity.5
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Sparsentan (DB12548)
- Weight
- Average: 592.76
Monoisotopic: 592.271941578 - Chemical Formula
- C32H40N4O5S
- Synonyms
- Sparsentan
- External IDs
- PS-433540
- PS433540
- RE-021
Pharmacology
- Indication
Sparsentan is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of disease progression.8
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Symptomatic treatment of Proteinuria •••••••••••• ••••• •• •••• •• ••••• ••••••• ••••••••••• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Sparsentan is a dual endothelin and angiotensin II receptor antagonist. At week 36, the exposure-response (E-R) relationship between sparsentan exposure and the percentage reduction from baseline in urine protein-to-creatinine ratio (UPCR) was not statistically significant over the observed sparsentan exposure range. E-R relationships were not statistically significant for any grade of hypotension or the worst grade of peripheral edema.5
In healthy subjects, sparsentan caused QTcF prolongation with a maximal mean effect of 8.8 msec at 800 mg and 8.1 msec at 1600 mg. The mechanism behind the observed QTc prolongation is unknown but is unlikely to be mediated via direct inhibition of hERG channels. At the recommended dose, no clinically relevant QTc prolongation is expected. The use of sparsentan may cause hepatotoxicity, embryo-fetal toxicity, hypotension, acute kidney injury, hyperkalemia, and fluid retention.5
- Mechanism of action
Sparsentan is a molecule that acts as a dual antagonist of the endothelin type A receptor (ETAR) and the angiotensin II (Ang II) type 1 receptor (AT1R).5 It possesses two clinically validated mechanisms of action and selectively blocks the action of two potent vasoconstrictor and mitogenic agents, Ang II and endothelin 1 (ET-1), at their respective receptors.2 ET-1 and Ang II contribute to the pathogenesis of immunoglobulin A nephropathy (IgAN), a condition characterized by the increased production of galactose-deficient IgA1 (Gd-IgA1) antibodies. Gd-IgA1 antibodies lead to mesangial cell activation and proliferation, which stimulates and is stimulated by ET-1 and Ang II production. The pathological cycle of IgAN results in a compromised glomerular filtration barrier and subsequent proteinuria and haematuria.6 By acting as both an angiotensin receptor blocker (ARB) and an endothelin receptor antagonist (ERA), sparsentan reduces proteinuria in patients with IgAN.1,3,6 Sparsentan has a high affinity for both ETAR (Ki= 12.8 nM) and AT1R (Ki=0.36 nM), and greater than 500-fold selectivity for these receptors over the endothelin type B and angiotensin II subtype 2 receptors.5
Target Actions Organism AEndothelin-1 receptor antagonistHumans AType-1 angiotensin II receptor antagonistHumans UType-2 angiotensin II receptor antagonistHumans - Absorption
Following administration of single doses of 200-1600 mg, the Cmax and AUC of sparsentan increase in a less than dose-proportional manner. Sparsentan has time-dependent pharmacokinetics, possibly due to it inducing its own metabolism over time, and at the approved recommended dosage, it reaches steady-state plasma levels within 7 days. Following a single oral dose of 400 mg, the Cmax, AUC and median time to peak plasma concentration of sparsentan are 6.97 μg/mL, 83 μg×h/mL, and 3 hours, respectively. Following daily doses of 400 mg sparsentan, the steady-state Cmax is 6.47 μg/mL, and the AUC is 63.6 μg×h/mL. The administration of a single oral dose (800 mg) of sparsentan with a high-fat, high-calorie meal (1000 kcal, 50% fat) increased the AUC and Cmax by 22% and 108%, respectively. With a single 200 mg dose, a high-fat, high-calorie meal did not have a clinically significant effect on sparsentan pharmacokinetics.5
- Volume of distribution
At the approved recommended dosage, sparsentan has an apparent volume of distribution at steady state of 61.4 L.5
- Protein binding
Sparsentan is more than 99% bound to human plasma proteins.5
- Metabolism
Sparsentan is mainly metabolized by cytochrome P450 3A.5
- Route of elimination
Sparsentan is mainly excreted through feces and urine. In healthy subjects given a single dose (400 mg) of radiolabeled sparsentan, approximately 80% of the dose was recovered in feces (9% unchanged) and 2% in urine (negligible amount unchanged). Within a 10-day collection period, 82% of the dosed radioactivity was recovered.5
- Half-life
Sparsentan has an estimated half-life of 9.6 hours at steady state.5
- Clearance
Sparsentan has a time-dependent clearance, possibly due to it inducing its own metabolism over time. Following the initial 400 mg dose, sparsentan has an apparent clearance of 3.88 L/h. At steady state, the apparent clearance increases to 5.11 L/h.5
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
No overdose experience has been reported with sparsentan. Doses up to 1600 mg/day and 400 mg/day have been given to healthy volunteers and patients, respectively. Overdose of sparsentan may result in decreased blood pressure. Provide standard supportive measures, as required, in case of an overdose. Since sparsentan is highly protein-bound, dyalisis may not be effective.5 A 2-year rat carcinogenicity study where male and female mice received 0.7 and 26 times the AUC at the maximum recommended human dose (MRHD), respectively, found no evidence of increased incidence of neoplasia. A 26-week transgenic mouse study reported similar results. In vitro bacteria reverse mutation and chromosomal aberration assays and an in vivo rat micronucleus study did not find evidence of mutagenicity or clastogenicity for sparsentan. Sparsentan did not lead to an impairment of fertility in male or female rats and monkeys.5
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Sparsentan can be increased when it is combined with Abametapir. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Sparsentan. Abrocitinib The serum concentration of Abrocitinib can be decreased when it is combined with Sparsentan. Aceclofenac The risk or severity of adverse effects can be increased when Aceclofenac is combined with Sparsentan. Acemetacin The risk or severity of adverse effects can be increased when Acemetacin is combined with Sparsentan. - Food Interactions
- Take before a meal. Sparsentan AUC and Cmax increase following the administration of a high fat, high calorie meal. Advise patients to take the full daily dose with water prior to the morning or evening meal. Maintain the same dosing pattern in relationship to meals.
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.- International/Other Brands
- Filspari (Travere Therapeutics)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Filspari Tablet, film coated 400 mg/1 Oral Travere Therapeutics, Inc. 2023-02-17 Not applicable US 
Filspari Tablet, film coated 200 mg/1 Oral Travere Therapeutics, Inc. 2023-02-17 Not applicable US
Categories
- Drug Categories
- Agents Acting on the Renin-Angiotensin System
- Amides
- Angiotensin 2 Receptor Blocker
- Angiotensin II receptor antagonists
- Angiotensin II Type 1 Receptor Blockers
- Angiotensin Receptor Antagonists
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (strength unknown)
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C19 Inducers (strength unknown)
- Cytochrome P-450 CYP2C9 Inducers
- Cytochrome P-450 CYP2C9 Inducers (strength unknown)
- 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 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Dual Endothelin Type A Receptor/Ang II Subtype 1 Receptor Antagonist (DEARA)
- Endothelin Receptor Antagonists
- OAT3/SLC22A8 Inhibitors
- OATP1B3 inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Sulfones
- Sulfur Compounds
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Biphenyls and derivatives
- Direct Parent
- Biphenyls and derivatives
- Alternative Parents
- Alpha amino acids and derivatives / Benzenesulfonamides / Benzenesulfonyl compounds / Benzylethers / Organosulfonamides / Imidazolinones / Imidolactams / Heteroaromatic compounds / Aminosulfonyl compounds / Isoxazoles show 9 more
- Substituents
- 2-imidazoline / Alpha-amino acid or derivatives / Amidine / Aminosulfonyl compound / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenesulfonamide / Benzenesulfonyl group / Benzylether show 26 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 9242RO5URM
- CAS number
- 254740-64-2
- InChI Key
- WRFHGDPIDHPWIQ-UHFFFAOYSA-N
- InChI
- InChI=1S/C32H40N4O5S/c1-5-7-14-29-33-32(17-10-11-18-32)31(37)36(29)20-24-15-16-26(25(19-24)21-40-6-2)27-12-8-9-13-28(27)42(38,39)35-30-22(3)23(4)41-34-30/h8-9,12-13,15-16,19H,5-7,10-11,14,17-18,20-21H2,1-4H3,(H,34,35)
- IUPAC Name
- 4'-({2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl}methyl)-N-(4,5-dimethyl-1,2-oxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide
- SMILES
- CCCCC1=NC2(CCCC2)C(=O)N1CC1=CC=C(C(COCC)=C1)C1=CC=CC=C1S(=O)(=O)NC1=NOC(C)=C1C
References
- General References
- Komers R, Gipson DS, Nelson P, Adler S, Srivastava T, Derebail VK, Meyers KE, Pergola P, MacNally ME, Hunt JL, Shih A, Trachtman H: Efficacy and Safety of Sparsentan Compared With Irbesartan in Patients With Primary Focal Segmental Glomerulosclerosis: Randomized, Controlled Trial Design (DUET). Kidney Int Rep. 2017 Mar 4;2(4):654-664. doi: 10.1016/j.ekir.2017.02.019. eCollection 2017 Jul. [Article]
- Davenport AP, Kuc RE, Southan C, Maguire JJ: New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res. 2018 Jun 27;67(Suppl 1):S37-S54. doi: 10.33549/physiolres.933872. [Article]
- Komers R, Diva U, Inrig JK, Loewen A, Trachtman H, Rote WE: Study Design of the Phase 3 Sparsentan Versus Irbesartan (DUPLEX) Study in Patients With Focal Segmental Glomerulosclerosis. Kidney Int Rep. 2020 Jan 8;5(4):494-502. doi: 10.1016/j.ekir.2019.12.017. eCollection 2020 Apr. [Article]
- Murugesan N, Gu Z, Fadnis L, Tellew JE, Baska RA, Yang Y, Beyer SM, Monshizadegan H, Dickinson KE, Valentine MT, Humphreys WG, Lan SJ, Ewing WR, Carlson KE, Kowala MC, Zahler R, Macor JE: Dual angiotensin II and endothelin A receptor antagonists: synthesis of 2'-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics. J Med Chem. 2005 Jan 13;48(1):171-9. doi: 10.1021/jm049548x. [Article]
- FDA Approved Drug Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- EMJ: The Dual Role of Endothelin-1 and Angiotensin II in Disease Progression of Focal Segmental Glomerulosclerosis and IgA Nephropathy (Symposium Review) [Link]
- Globe News Wire: Travere Therapeutics Announces FDA Accelerated Approval of FILSPARI (sparsentan), the First and Only Non-immunosuppressive Therapy for the Reduction of Proteinuria in IgA Nephropathy [Link]
- FDA Approved Drug Products: Filspari (sparsentan) tablets for oral use (September 2024) [Link]
- Travere Therapeutics News Release: Travere Therapeutics Announces Full FDA Approval of FILSPARI® (sparsentan), the Only Non-Immunosuppressive Treatment that Significantly Slows Kidney Function Decline in IgA Nephropathy [Link]
- External Links
- PubChem Compound
- 10257882
- PubChem Substance
- 347828773
- ChemSpider
- 8433365
- BindingDB
- 50175523
- ChEMBL
- CHEMBL539423
- Wikipedia
- Sparsentan
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 data3 Active Not Recruiting Treatment Focal Segmental Glomerulosclerosis (FSGS) 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Immunoglobulin A Nephropathy 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Cardiovascular Disease (CVD) / Kidney Diseases 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Autoimmune Disorder / Glomerulonephritis / Glomerulonephritis , IGA / Immune System Diseases / Immunoglobulin A Nephropathy / Kidney Diseases 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Immunoglobulin A Nephropathy 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 200 mg/1 Tablet, film coated Oral 400 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9993461 No 2018-06-12 2030-03-29 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 0.055 mg/mL FDA label - Predicted Properties
Property Value Source Water Solubility 0.0122 mg/mL ALOGPS logP 5.56 ALOGPS logP 6.06 Chemaxon logS -4.7 ALOGPS pKa (Strongest Acidic) 5.69 Chemaxon pKa (Strongest Basic) 3.52 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 114.1 Å2 Chemaxon Rotatable Bond Count 11 Chemaxon Refractivity 164.45 m3·mol-1 Chemaxon Polarizability 66.65 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 242.77936 predictedDeepCCS 1.0 (2019) [M+H]+ 244.78932 predictedDeepCCS 1.0 (2019) [M+Na]+ 250.70229 predictedDeepCCS 1.0 (2019)
Targets
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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
- Antagonist
- General Function
- Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3
- Specific Function
- endothelin receptor activity
- Gene Name
- EDNRA
- Uniprot ID
- P25101
- Uniprot Name
- Endothelin-1 receptor
- Molecular Weight
- 48721.76 Da
References
- Murugesan N, Gu Z, Fadnis L, Tellew JE, Baska RA, Yang Y, Beyer SM, Monshizadegan H, Dickinson KE, Valentine MT, Humphreys WG, Lan SJ, Ewing WR, Carlson KE, Kowala MC, Zahler R, Macor JE: Dual angiotensin II and endothelin A receptor antagonists: synthesis of 2'-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics. J Med Chem. 2005 Jan 13;48(1):171-9. doi: 10.1021/jm049548x. [Article]
- Komers R, Gipson DS, Nelson P, Adler S, Srivastava T, Derebail VK, Meyers KE, Pergola P, MacNally ME, Hunt JL, Shih A, Trachtman H: Efficacy and Safety of Sparsentan Compared With Irbesartan in Patients With Primary Focal Segmental Glomerulosclerosis: Randomized, Controlled Trial Design (DUET). Kidney Int Rep. 2017 Mar 4;2(4):654-664. doi: 10.1016/j.ekir.2017.02.019. eCollection 2017 Jul. [Article]
- Davenport AP, Kuc RE, Southan C, Maguire JJ: New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res. 2018 Jun 27;67(Suppl 1):S37-S54. doi: 10.33549/physiolres.933872. [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 Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Receptor for angiotensin II, a vasoconstricting peptide, which acts as a key regulator of blood pressure and sodium retention by the kidney (PubMed:15611106, PubMed:1567413, PubMed:25913193, PubMed:26420482, PubMed:30639100, PubMed:32079768, PubMed:8987975). The activated receptor in turn couples to G-alpha proteins G(q) (GNAQ, GNA11, GNA14 or GNA15) and thus activates phospholipase C and increases the cytosolic Ca(2+) concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C (PubMed:15611106)
- Specific Function
- angiotensin type I receptor activity
- Gene Name
- AGTR1
- Uniprot ID
- P30556
- Uniprot Name
- Type-1 angiotensin II receptor
- Molecular Weight
- 41060.53 Da
References
- Davenport AP, Kuc RE, Southan C, Maguire JJ: New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res. 2018 Jun 27;67(Suppl 1):S37-S54. doi: 10.33549/physiolres.933872. [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 Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- Curator comments
- Sparsentan may bind to AT2R with very low affinity. It is unlikely to contribute to the drug’s pharmacological effect, because sparsentan has greater than 500-fold selectivity for the type-1 angiotensin II receptor over the type-2 angiotensin II receptor.
- General Function
- Receptor for angiotensin II, a vasoconstricting peptide (PubMed:28379944, PubMed:29967536, PubMed:31899086, PubMed:8185599). Signals primarily via a non-canonical G-protein- and beta-arrestin independent pathways (PubMed:28379944). Cooperates with MTUS1 to inhibit ERK2 activation and cell proliferation (PubMed:15123706)
- Specific Function
- angiotensin type II receptor activity
- Gene Name
- AGTR2
- Uniprot ID
- P50052
- Uniprot Name
- Type-2 angiotensin II receptor
- Molecular Weight
- 41183.45 Da
References
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- FDA Approved Drug Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- 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
- FDA Approved Drug Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- 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
- FDA Approved Drug Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- 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
- FDA Approved Drug Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- FDA Approved Drug Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- FDA Approved Drug Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
- FDA Approved Drug Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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 Products: FILSPARI (sparsentan) tablets for oral use (February 2023) [Link]
Drug created at October 20, 2016 22:48 / Updated at October 03, 2024 06:54