Velpatasvir (original) (raw)
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Description
A medication used to treat some types of chronic hepatitis C infections.
Description
A medication used to treat some types of chronic hepatitis C infections.
DrugBank ID
DB11613
Type
Small Molecule
US Approved
YES
Other Approved
YES
Therapeutic Categories
Mechanism of Action
Summary
Velpatasvir is a NS5A inhibitor used to treat chronic hepatitis C infections in patients without cirrhosis or with compensated cirrhosis.
Brand Names
Epclusa, Vosevi
Generic Name
Velpatasvir
DrugBank Accession Number
DB11613
Background
Velpatasvir is a Direct-Acting Antiviral (DAA) medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients 8. Velpatasvir acts as a defective substrate for NS5A (Non-Structural Protein 5A), a non-enzymatic viral protein that plays a key role in Hepatitis C Virus replication, assembly, and modulation of host immune responses 3. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as velpatasvir. Notably, velpatasvir has a significantly higher barrier to resistance than the first generation NS5A inhibitors, such as Ledipasvir and Daclatasvir, making it a highly potent and reliable alternative for treatment of chronic Hepatitis C 6.
In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Velpatasvir as first line therapy in combination with sofosbuvir for all six genotypes of Hepatitis C 8. Velpatasvir is currently only available within a fixed dose combination product as Epclusa with Sofosbuvir, another direct acting antiviral. Goals of therapy for Epclusa include the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality and risk of requiring a liver transplant 5.
Since June 2016, Velpatasvir has been available as a fixed dose combination product with Sofosbuvir, as the commercially available product Epclusa. Epclusa is the first combination HCV product indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis. It is also currently the most potent HCV antiviral medication on the market with a sustained virologic response (SVR) after 12 weeks of therapy of 93-99% depending on genotype and level of cirrhosis and a high barrier to resistance 8. Both Canadian and American guidelines list Epclusa as a first line recommendation for all genotypes of HCV 8,5.
Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 883.019
Monoisotopic: 882.406460731
Chemical Formula
C49H54N8O8
Synonyms
- Velpatasvir
- Velpatasvirum
- GS 5816
- GS-5816
- GS5816
Indication
Velpatasvir is used in combination therapy with other antiviral medications to treat chronic hepatitis C virus (HCV) infected patients with HCV genoptypes 1-6, and to treat HCV and HIV co-infected patients. Depending on the level of cirrhosis or decompensation, combination therapy can also include therapy with Ribavirin.
When used in combination with Sofosbuvir as the combination product Epclusa, Velpatasvir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis, or in combination with Ribavirin if associated with decompensated cirrhosis Label.
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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics
Velpatasvir is a small molecule direct-acting antiviral used in the treatment of hepatitis C in combination with sofosbuvir. Velpatasvir prevents viral replication by inhibiting non-structural protein 5A (NS5A) 4.
At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent Label.
Mechanism of action
Velpatasvir's mechanism of action is likely similar to other selective NS5A inhibitors which bind domain I of NS5A consisting of amino acids 33-202 1. NS5A inhibitors compete with RNA for binding at this site. It is also thought that NS5A inhibitors bind the target during its action in replication when the binding site is exposed 2. Inhibition of NS5A is also known to produce redistribution of the protein to lipid droplets. The exact role of NS5A in RNA replication is not yet understood although it is known to be an important component.
| Target | Actions | Organism |
|---|---|---|
| ANonstructural protein 5A | inhibitor | Hepatitis C Virus |
Absorption
Oral bioavailability of 25-30% 3.
Volume of distribution
1.4-1.6 L/kg 3.
Protein binding
>99.5% bound to plasma proteins Label.
Metabolism
Some metabolism by CYP2B6, CYP2C8, and CYP3A4 3.
Route of elimination
94% excreted in feces with 77% as parent compound. 0.4% excreted in urine Label.
Half-life
15h Label.
Clearance
Estimated 0.12 L/h/kg [A19175.
Adverse Effects
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Toxicity
No indication of carcinogenicity or impairment of fertility/fetal viability Label.
Pathways
Not Available
Not Available
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 software | |
| Abametapir | The serum concentration of Velpatasvir can be increased when it is combined with Abametapir. |
| Abatacept | The metabolism of Velpatasvir can be increased when combined with Abatacept. |
| Abemaciclib | The serum concentration of Abemaciclib can be increased when it is combined with Velpatasvir. |
| Abiraterone | The metabolism of Velpatasvir can be decreased when combined with Abiraterone. |
| Abrocitinib | The serum concentration of Velpatasvir can be increased when it is combined with Abrocitinib. |
Food Interactions
- Avoid St. John's Wort.
- Take with or without food. Multiple different combination products contain velpatasvir. Take Epclusa with or without food. Take Vosevi with food.
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Mixture Products
ATC Codes
J05AP55 — Sofosbuvir and velpatasvir
- J05AP — Antivirals for treatment of HCV infections
- J05A — DIRECT ACTING ANTIVIRALS
- J05 — ANTIVIRALS FOR SYSTEMIC USE
- J — ANTIINFECTIVES FOR SYSTEMIC USE J05AP56 — Sofosbuvir, velpatasvir and voxilaprevir
- J05AP — Antivirals for treatment of HCV infections
- J05A — DIRECT ACTING ANTIVIRALS
- J05 — ANTIVIRALS FOR SYSTEMIC USE
- J — ANTIINFECTIVES FOR SYSTEMIC USE
Drug Categories
- Acids, Acyclic
- Anti-Infective Agents
- Antiinfectives for Systemic Use
- Antiviral Agents
- Antivirals for Systemic Use
- Antivirals for treatment of HCV infections
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP2B6 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Direct Acting Antivirals
- Hepatitis C Virus NS5A Inhibitor
- Heterocyclic Compounds, Fused-Ring
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B3 inhibitors
- Organic Anion Transporting Polypeptide 1B1 Inhibitors
- Organic Anion Transporting Polypeptide 1B3 Inhibitors
- Organic Anion Transporting Polypeptide 2B1 Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Pyrans
- Treatments for Hepatitis C
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as naphthopyrans. These are compounds containing a pyran ring fused to a naphthalene moiety. Furan is a 6 membered-ring non-aromatic ring with five carbon and one oxygen atoms. Naphthalene is a polycyclic aromatic hydrocarbon made up of two fused benzene rings.
Kingdom
Super Class
Class
Sub Class
Not Available
Direct Parent
Alternative Parents
Dibenzopyrans / Valine and derivatives / Alpha amino acid amides / Phenylacetamides / 2-benzopyrans / Naphthalenes / Benzimidazoles / N-acylpyrrolidines / Alkyl aryl ethers / Pyrans / Tertiary carboxylic acid amides / Methylcarbamates / Imidazoles / Heteroaromatic compounds / Azacyclic compounds / Dialkyl ethers / Oxacyclic compounds / Carbonyl compounds / Hydrocarbon derivatives / Organic oxides / Organonitrogen compounds / Organopnictogen compounds show 12 more
Substituents
1-benzopyran / 2-benzopyran / Alkyl aryl ether / Alpha-amino acid amide / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzimidazole / Benzopyran / Carbamic acid ester / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Dialkyl ether / Dibenzopyran / Ether / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Methylcarbamate / Monocyclic benzene moiety / N-acylpyrrolidine / Naphthalene / Naphthopyran / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Phenylacetamide / Pyran / Pyrrolidine / Tertiary carboxylic acid amide / Valine or derivatives show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
- Hepatitis C Virus
UNII
CAS number
1377049-84-7
InChI Key
FHCUMDQMBHQXKK-CDIODLITSA-N
InChI
InChI=1S/C49H54N8O8/c1-26(2)41(54-48(60)63-5)47(59)57-27(3)12-17-38(57)45-51-36-16-14-30-20-35-33-15-13-31(19-32(33)25-65-40(35)21-34(30)43(36)53-45)37-22-50-44(52-37)39-18-28(24-62-4)23-56(39)46(58)42(55-49(61)64-6)29-10-8-7-9-11-29/h7-11,13-16,19-22,26-28,38-39,41-42H,12,17-18,23-25H2,1-6H3,(H,50,52)(H,51,53)(H,54,60)(H,55,61)/t27-,28-,38-,39-,41-,42+/m0/s1
IUPAC Name
methyl N-[(1R)-2-[(2S,4S)-2-(5-{6-[(2S,5S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]-5-methylpyrrolidin-2-yl]-21-oxa-5,7-diazapentacyclo[11.8.0.0^{3,11}.0^{4,8}.0^{14,19}]henicosa-1,3(11),4(8),6,9,12,14,16,18-nonaen-17-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl]carbamate
SMILES
COC[C@H]1C[C@H](N(C1)C(=O)[C@H](NC(=O)OC)C1=CC=CC=C1)C1=NC=C(N1)C1=CC=C2C(COC3=CC4=C(C=CC5=C4NC(=N5)[C@@H]4CC[C@H](C)N4C(=O)[C@@H](NC(=O)OC)C(C)C)C=C23)=C1
General References
- Ascher DB, Wielens J, Nero TL, Doughty L, Morton CJ, Parker MW: Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. Sci Rep. 2014 Apr 23;4:4765. doi: 10.1038/srep04765. [Article]
- Targett-Adams P, Graham EJ, Middleton J, Palmer A, Shaw SM, Lavender H, Brain P, Tran TD, Jones LH, Wakenhut F, Stammen B, Pryde D, Pickford C, Westby M: Small molecules targeting hepatitis C virus-encoded NS5A cause subcellular redistribution of their target: insights into compound modes of action. J Virol. 2011 Jul;85(13):6353-68. doi: 10.1128/JVI.00215-11. Epub 2011 Apr 20. [Article]
- Mogalian E, German P, Kearney BP, Yang CY, Brainard D, Link J, McNally J, Han L, Ling J, Mathias A: Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects. Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: e02084-16. doi: 10.1128/AAC.02084-16. Print 2017 May. [Article]
- Lawitz E, Freilich B, Link J, German P, Mo H, Han L, Brainard DM, McNally J, Marbury T, Rodriguez-Torres M: A phase 1, randomized, dose-ranging study of GS-5816, a once-daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus. J Viral Hepat. 2015 Dec;22(12):1011-9. doi: 10.1111/jvh.12435. Epub 2015 Jul 16. [Article]
- Myers RP, Shah H, Burak KW, Cooper C, Feld JJ: An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol. 2015 Jan-Feb;29(1):19-34. Epub 2015 Jan 13. [Article]
- Lawitz EJ, Dvory-Sobol H, Doehle BP, Worth AS, McNally J, Brainard DM, Link JO, Miller MD, Mo H: Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5368-78. doi: 10.1128/AAC.00763-16. Print 2016 Sep. [Article]
- Epclusa FDA Approval Announcement [Link]
- American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
External Links
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PubChem Compound
PubChem Substance
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ChEMBL
ZINC
PharmGKB
RxList
Drugs.com
Wikipedia
FDA label
MSDS
Clinical Trials
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Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
| Form | Route | Strength |
|---|---|---|
| Pellet | Oral | |
| Tablet | Oral | |
| Tablet, film coated | Oral | |
| Tablet, coated | Oral |
Prices
Not Available
Patents
| Patent Number | Pediatric Extension | Approved | Expires (estimated) | Region |
|---|---|---|---|---|
| US7964580 | Yes | 2011-06-21 | 2029-09-26 |  |
| US8334270 | Yes | 2012-12-18 | 2028-09-21 | |
| US8633309 | Yes | 2014-01-21 | 2029-09-26 | |
| US8618076 | Yes | 2013-12-31 | 2031-06-11 | |
| US8735372 | Yes | 2014-05-27 | 2028-09-21 | |
| US8580765 | Yes | 2013-11-12 | 2028-09-21 | |
| US8889159 | Yes | 2014-11-18 | 2029-09-26 | |
| US9085573 | Yes | 2015-07-21 | 2028-09-21 | |
| US9284342 | Yes | 2016-03-15 | 2031-03-13 | |
| US8940718 | Yes | 2015-01-27 | 2033-05-16 | |
| US8575135 | Yes | 2013-11-05 | 2034-05-05 | |
| US8921341 | Yes | 2014-12-30 | 2033-05-16 | |
| US9585906 | No | 2017-03-07 | 2028-03-21 | |
| US9296782 | No | 2016-03-29 | 2034-07-17 | |
| US9757406 | Yes | 2017-09-12 | 2034-07-30 | |
| US9868745 | No | 2018-01-16 | 2032-11-16 | |
| US10086011 | Yes | 2018-10-02 | 2034-07-30 | |
| US8957046 | No | 2015-02-17 | 2028-03-21 | |
| US10912814 | No | 2021-02-09 | 2037-06-01 | |
| US11116783 | Yes | 2021-09-14 | 2034-07-30 | |
| US11338007 | Yes | 2017-12-01 | 2037-12-01 | |
| US11707479 | Yes | 2014-07-30 | 2034-07-30 | |
State
Solid
Experimental Properties
Not Available
Predicted Properties
| Property | Value | Source |
|---|---|---|
| Water Solubility | 0.00585 mg/mL | ALOGPS |
| logP | 5.39 | ALOGPS |
| logP | 5.11 | Chemaxon |
| logS | -5.2 | ALOGPS |
| pKa (Strongest Acidic) | 11.14 | Chemaxon |
| pKa (Strongest Basic) | 5.97 | Chemaxon |
| Physiological Charge | 0 | Chemaxon |
| Hydrogen Acceptor Count | 8 | Chemaxon |
| Hydrogen Donor Count | 4 | Chemaxon |
| Polar Surface Area | 193.1 Å2 | Chemaxon |
| Rotatable Bond Count | 13 | Chemaxon |
| Refractivity | 240.57 m3·mol-1 | Chemaxon |
| Polarizability | 97.05 Å3 | Chemaxon |
| Number of Rings | 9 | 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
Mass Spec (NIST)
Not Available
Spectra
| Spectrum | Spectrum Type | Splash Key |
|---|---|---|
| Predicted MS/MS Spectrum - 10V, Positive (Annotated) | Predicted LC-MS/MS | splash10-01e9-0200000590-24093dc5374d2023160e |
| Predicted MS/MS Spectrum - 10V, Negative (Annotated) | Predicted LC-MS/MS | splash10-0229-3200002490-0dc768065484be0b4c16 |
| Predicted MS/MS Spectrum - 20V, Positive (Annotated) | Predicted LC-MS/MS | splash10-0fb9-1000003970-ed3c6b83279a3e8dcd8a |
| Predicted MS/MS Spectrum - 20V, Negative (Annotated) | Predicted LC-MS/MS | splash10-0296-3000001950-987503e33edc80166cb1 |
| Predicted MS/MS Spectrum - 40V, Positive (Annotated) | Predicted LC-MS/MS | splash10-0ac0-9510001250-983e4230aae36bbc1820 |
| Predicted MS/MS Spectrum - 40V, Negative (Annotated) | Predicted LC-MS/MS | splash10-01po-1121007940-b7d276d88cf7c3ed5de8 |
Chromatographic Properties
Collision Cross Sections (CCS)
| Adduct | CCS Value (Å2) | Source type | Source |
|---|---|---|---|
| [M-H]- | 273.1923 | predicted | DeepCCS 1.0 (2019) |
| [M+H]+ | 274.96066 | predicted | DeepCCS 1.0 (2019) |
| [M+Na]+ | 281.0851 | predicted | DeepCCS 1.0 (2019) |
Targets
Enzymes
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
- VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir) FDA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Transporters
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
- Mogalian E, German P, Kearney BP, Yang CY, Brainard D, McNally J, Moorehead L, Mathias A: Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir. Clin Pharmacokinet. 2016 May;55(5):605-13. doi: 10.1007/s40262-015-0334-7. [Article]
- Geddawy A, Ibrahim YF, Elbahie NM, Ibrahim MA: Direct Acting Anti-hepatitis C Virus Drugs: Clinical Pharmacology and Future Direction. J Transl Int Med. 2017 Mar 31;5(1):8-17. doi: 10.1515/jtim-2017-0007. eCollection 2017 Mar. [Article]
- FDA label Sofusbuvir and Velpatasvir [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
Uniprot Name
Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight
72313.47 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Transporter
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
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Transporter
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
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Transporter
General Function
Mediates the Na(+)-independent transport of steroid sulfate conjugates and other specific organic anions (PubMed:10873595, PubMed:11159893, PubMed:11932330, PubMed:12724351, PubMed:14610227, PubMed:16908597, PubMed:18501590, PubMed:20507927, PubMed:22201122, PubMed:23531488, PubMed:25132355, PubMed:26383540, PubMed:27576593, PubMed:28408210, PubMed:29871943, PubMed:34628357). Responsible for the transport of estrone 3-sulfate (E1S) through the basal membrane of syncytiotrophoblast, highlighting a potential role in the placental absorption of fetal-derived sulfated steroids including the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S) (PubMed:11932330, PubMed:12409283). Also facilitates the uptake of sulfated steroids at the basal/sinusoidal membrane of hepatocytes, therefore accounting for the major part of organic anions clearance of liver (PubMed:11159893). Mediates the intestinal uptake of sulfated steroids (PubMed:12724351, PubMed:28408210). Mediates the uptake of the neurosteroids DHEA-S and pregnenolone sulfate (PregS) into the endothelial cells of the blood-brain barrier as the first step to enter the brain (PubMed:16908597, PubMed:25132355). Also plays a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May act as a heme transporter that promotes cellular iron availability via heme oxygenase/HMOX2 and independently of TFRC (PubMed:35714613). Also transports heme by-product coproporphyrin III (CPIII), and may be involved in their hepatic disposition (PubMed:26383540). Mediates the uptake of other substrates such as prostaglandins D2 (PGD2), E1 (PGE1) and E2 (PGE2), taurocholate, L-thyroxine, leukotriene C4 and thromboxane B2 (PubMed:10873595, PubMed:14610227, PubMed:19129463, PubMed:29871943, Ref.25). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable). 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:14610227, PubMed:19129463, PubMed:22201122). The exact transport mechanism has not been yet deciphered but most likely involves an anion exchange, coupling the cellular uptake of organic substrate with the efflux of an anionic compound (PubMed:19129463, PubMed:20507927, PubMed:26277985). Hydrogencarbonate/HCO3(-) acts as a probable counteranion that exchanges for organic anions (PubMed:19129463). Cytoplasmic glutamate may also act as counteranion in the placenta (PubMed:26277985). An inwardly directed proton gradient has also been proposed as the driving force of E1S uptake with a (H(+):E1S) stoichiometry of (1:1) (PubMed:20507927)
Specific Function
bile acid transmembrane transporter activity
Gene Name
SLCO2B1
Uniprot ID
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76697.93 Da
Drug created at August 05, 2016 23:48 / Updated at February 21, 2021 18:53