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Identification
- Summary
Aprocitentan is an endothelin receptor antagonist used for the treatment of uncontrolled hypertension in patients inadequately controlled on other treatments.
- Brand Names
- Tryvio
- Generic Name
- Aprocitentan
- DrugBank Accession Number
- DB15059
- Background
Aprocitentan is a dual antagonist of endothelin receptors A and B used for treatment-resistant hypertension. It is the active metabolite of macitentan.
Approximately 10-15% of patients with hypertension have resistant hypertension, defined as uncontrolled high blood pressure despite the combined use of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses.1 Patients with resistant hypertension are at an increased risk of cardiovascular and renal events1 and have traditionally had limited additional treatment options. Endothelin receptor antagonism provides a novel therapeutic pathway for the management of patients with resistant hypertension.1,5
Aprocitentan was approved by the FDA in March 2024 for the treatment of hypertension in patients inadequately controlled with standard therapy.5 It was the first antihypertensive employing a novel mechanism to be approved in almost 40 years.5
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Aprocitentan (DB15059)
- Weight
- Average: 546.19
Monoisotopic: 543.9164 - Chemical Formula
- C16H14Br2N6O4S
- Synonyms
- Aprocitentan
- External IDs
- ACT-132577
Pharmacology
- Indication
Aprocitentan, in combination with other antihypertensive medications, is indicated to lower blood pressure in adult patients who are not adequately controlled on other therapies.6
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 Used in combination to treat Hypertension •••••••••••• •••••• - 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
Aprocitentan exerts its pharmacologic effects by antagonizing receptors, ETA and ETB, which play a role in the pathogenesis of hypertension.6 In the PRECISION trial, aprocitentan demonstrated superiority to placebo in reducing both sitting systolic and diastolic blood pressures, with a mean reduction in sitting trough blood pressure of approximately 4 mmHg greater than placebo.6 Most of the antihypertensive effect of aprocitentan occurs within the first two weeks of treatment.6
Based on data from animal reproduction studies with other endothelin receptor antagonists, aprocitentan can cause fetal harm when administered during pregnancy. Prior to initiating treatment with aprocitentan, pregnancy should be excluded and acceptable contraceptive methods employed. Patients should monitor for pregnancy monthly and use effective contraception during treatment and for one month after discontinuation. Because of the significant risk of embryo-fetal toxicity, aprocitentan is only available through a restricted program called the Tryvio REMS.6
- Mechanism of action
Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system. It is produced constitutively by vascular endothelial cells to maintain vascular tone and is found in a variety of other cells including vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages, neurons, and epithelial cells in the lungs and kidneys.1 ET-1 acts on two receptors, ETA and ETB, located on vascular smooth muscle cells and endothelial cells which serve to regulate blood pressure by inducing vasoconstriction or vasodilation. ET-1 is an extremely potent vasoconstrictor that works primarily via interactions with the ETA receptor and, under pathologic conditions, further induces vasoconstriction via interactions with ETB2.1 The overexpression of both ET-1 and ET receptors has been shown in a variety of pathologies, including essential hypertension, pulmonary arterial hypertension, chronic kidney disease, and diabetes mellitus.1
Aprocitentan is a dual endothelin receptor antagonist that inhibits the binding of ET-1 to both ETA and ETB receptors.6 This inhibition mitigates the hypertensive effects of ET-1 overexpression, including endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis.6
Target Actions Organism AEndothelin-1 receptor antagonistHumans AEndothelin receptor type B antagonistHumans - Absorption
The absolute oral bioavailability of aprocitentan is unknown.6 The mean Cmax and AUC0-tau following a single oral dose of 25mg are approximately 1.3 mcg/mL and 23 mcg.h/mL, respectively, with a Tmax between 4-5 hours.6
- Volume of distribution
The apparent volume of distribution of aprocitentan is approximately 20 L.6
- Protein binding
Aprocitentan is highly (>99%) protein-bound in plasma, primarily to albumin.6
- Metabolism
Aprocitentan is primarily metabolized by UGT1A1- and UGT2B7-mediated N-glucosidation and non-enzymatic hydrolysis.6,4
- Route of elimination
Following the administration of a single radiolabeled dose of aprocitentan, approximately 52% of the dose was eliminated via urine (0.2% unchanged) and 25% via feces (6.8% unchanged).6
- Half-life
The effective half-life of aprocitentan is approximately 41 hours.6
- Clearance
The apparent clearance of aprocitentan is approximately 0.3 L/h.6
- Adverse Effects
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According to prescribing information, aprocitentan has been administered in single doses up to 600 mg, and as multiple doses of up to 100 mg daily, in healthy subjects (48- and 8-fold the recommended dose, respectively).6 Observed symptoms of overdosage included headache, nasal congestion, nausea, and upper respiratory tract infection. In the event of an overdose, standard supportive treatment should be employed as clinically indicated. As aprocitentan is highly protein-bound, dialysis is unlikely to be effective.6
- 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 softwareAbaloparatide Abaloparatide may increase the hypotensive activities of Aprocitentan. Acebutolol Acebutolol may increase the hypotensive activities of Aprocitentan. Aceclofenac The therapeutic efficacy of Aprocitentan can be decreased when used in combination with Aceclofenac. Acemetacin The therapeutic efficacy of Aprocitentan can be decreased when used in combination with Acemetacin. Acetylsalicylic acid Acetylsalicylic acid may decrease the antihypertensive activities of Aprocitentan. - Food Interactions
- Take with or without food. Co-administration with food does not appear to alter the pharmacokinetics of aprocitentan to a clinically significant extent.
Products
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Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tryvio Tablet, film coated 12.5 mg/1 Oral Idorsia Pharmaceuticals Deutschland Gmb H 2024-03-20 Not applicable US 
Tryvio Tablet, film coated 12.5 mg/1 Oral Idorsia Pharmaceuticals Deutschland Gmb H 2024-03-20 Not applicable US
Categories
- ATC Codes
- C02KN01 — Aprocitentan
- Drug Categories
- Amides
- Antihypertensive Agents
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- BSEP/ABCB11 Inhibitors
- Cytochrome P-450 CYP2C18 Inhibitors
- Cytochrome P-450 CYP2C18 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- 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 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Endothelin Receptor Antagonists
- P-glycoprotein substrates
- Sulfones
- Sulfur Compounds
- UGT1A1 Inhibitors
- UGT1A1 Substrates
- UGT2B7 Inhibitors
- UGT2B7 substrates
- Classification
- Not classified
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- MZI81HV01P
- CAS number
- 1103522-45-7
- InChI Key
- DKULOVKANLVDEA-UHFFFAOYSA-N
- InChI
- InChI=1S/C16H14Br2N6O4S/c17-11-3-1-10(2-4-11)13-14(24-29(19,25)26)22-9-23-15(13)27-5-6-28-16-20-7-12(18)8-21-16/h1-4,7-9H,5-6H2,(H2,19,25,26)(H,22,23,24)
- IUPAC Name
- N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]aminosulfonamide
- SMILES
- NS(=O)(=O)NC1=C(C(OCCOC2=NC=C(Br)C=N2)=NC=N1)C1=CC=C(Br)C=C1
References
- Synthesis Reference
Martin Bolli, Christoph Boss, Alexander Treiber. " 4-pyrimidinesulfamide derivative ", US Patent US8324232B2.
- General References
- Heidari Nejad S, Azzam O, Schlaich MP: Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension. Curr Hypertens Rep. 2023 Oct;25(10):343-352. doi: 10.1007/s11906-023-01259-z. Epub 2023 Aug 11. [Article]
- Clozel M: Aprocitentan and the endothelin system in resistant hypertension. Can J Physiol Pharmacol. 2022 Jul 1;100(7):573-583. doi: 10.1139/cjpp-2022-0010. Epub 2022 Apr 3. [Article]
- Fontes MSC, Dingemanse J, Halabi A, Tomaszewska-Kiecana M, Sidharta PN: Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment. Sci Rep. 2022 Nov 9;12(1):19067. doi: 10.1038/s41598-022-22470-z. [Article]
- Sidharta PN, Fischer H, Dingemanse J: Absorption, Distribution, Metabolism, and Excretion of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Humans. Curr Drug Metab. 2021;22(5):399-410. doi: 10.2174/1389200222666210204202815. [Article]
- American Journal of Managed Care: FDA Approves Idorsia's Tryvio for Resistant Hypertension [Link]
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- External Links
- ChemSpider
- 25027753
- BindingDB
- 50395672
- 2679059
- ChEBI
- 76609
- ChEMBL
- CHEMBL2165326
- ZINC
- ZINC000095553608
- Wikipedia
- Aprocitentan
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 Completed Treatment Resistant Hypertension 1 somestatus stop reason just information to hide 3 Withdrawn Treatment Hypertension / Renal Insufficiency,Chronic 1 somestatus stop reason just information to hide 2 Completed Treatment Hypertension, Essential Hypertension 1 somestatus stop reason just information to hide 1 Completed Other Healthy Volunteers (HV) 7 somestatus stop reason just information to hide 1 Completed Other Healthy Volunteers (HV) / Hepatic Impairment (HI) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 12.5 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11787782 No 2018-03-02 2038-03-02 US US11680058 No 2018-07-26 2038-07-26 US US11174247 No 2017-11-06 2037-11-06 US US8324232 No 2009-09-21 2029-09-21 US US10919881 No 2018-02-26 2038-02-26 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Insoluble FDA Label - Predicted Properties
Property Value Source Water Solubility 0.014 mg/mL ALOGPS logP 2.85 ALOGPS logP 2.58 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 7.79 Chemaxon pKa (Strongest Basic) 3.26 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 9 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 142.21 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 112.81 m3·mol-1 Chemaxon Polarizability 44.36 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 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)
Not Available
Targets
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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
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system
- Specific Function
- endothelin receptor activity
- Gene Name
- EDNRB
- Uniprot ID
- P24530
- Uniprot Name
- Endothelin receptor type B
- Molecular Weight
- 49643.255 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1A1
- Molecular Weight
- 59590.91 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:10702251, PubMed:15470161, PubMed:15472229, PubMed:17442341, PubMed:18674515, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:23756265, PubMed:26220143). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15470161, PubMed:18674515, PubMed:23756265). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol, estriol, catechol estrogens) (PubMed:15472229, PubMed:17442341, PubMed:18719240, PubMed:19022937, PubMed:2159463, PubMed:23288867, PubMed:26220143). Also regulates the levels of retinoic acid, a major metabolite of vitamin A involved in apoptosis, cellular growth and differentiation, and embryonic development (PubMed:10702251). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161)
- Specific Function
- glucuronosyltransferase activity
- Gene Name
- UGT2B7
- Uniprot ID
- P16662
- Uniprot Name
- UDP-glucuronosyltransferase 2B7
- Molecular Weight
- 60720.15 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- InhibitorInducer
- 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: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- 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: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in retinoid metabolism. Hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may modulate atRA signaling and clearance. 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 (CPR; NADPH-ferrihemoprotein reductase)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C18
- Uniprot ID
- P33260
- Uniprot Name
- Cytochrome P450 2C18
- Molecular Weight
- 55710.075 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- 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: Tryvio (aprocitentan) tablets for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeostasis and consequently to lipid homeostasis through regulation of biliary lipid secretion in a bile salts dependent manner (PubMed:15791618, PubMed:16332456, PubMed:18985798, PubMed:19228692, PubMed:20010382, PubMed:20398791, PubMed:22262466, PubMed:24711118, PubMed:29507376, PubMed:32203132). Transports taurine-conjugated bile salts more rapidly than glycine-conjugated bile salts (PubMed:16332456). Also transports non-bile acid compounds, such as pravastatin and fexofenadine in an ATP-dependent manner and may be involved in their biliary excretion (PubMed:15901796, PubMed:18245269)
- Specific Function
- ABC-type bile acid transporter activity
- Gene Name
- ABCB11
- Uniprot ID
- O95342
- Uniprot Name
- Bile salt export pump
- Molecular Weight
- 146405.83 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- As a major transporter of conjugated bile salts from plasma into the hepatocyte, it plays a key role in the enterohepatic circulation of bile salts necessary for the solubilization and absorption of dietary fat and fat-soluble vitamins (PubMed:14660639, PubMed:24867799, PubMed:34060352, PubMed:8132774). It is strictly dependent on the extracellular presence of sodium (PubMed:14660639, PubMed:24867799, PubMed:34060352, PubMed:8132774). It exhibits broad substrate specificity and transports various bile acids, such as taurocholate, cholate, as well as non-bile acid organic compounds, such as estrone sulfate (PubMed:14660639, PubMed:34060352). Works collaboratively with the ileal transporter (NTCP2), the organic solute transporter (OST), and the bile salt export pump (BSEP), to ensure efficacious biological recycling of bile acids during enterohepatic circulation (PubMed:33222321)
- Specific Function
- bile acid
- Gene Name
- SLC10A1
- Uniprot ID
- Q14973
- Uniprot Name
- Hepatic sodium/bile acid cotransporter
- Molecular Weight
- 38118.64 Da
References
- FDA Approved Drug Products: Tryvio (aprocitentan) tablets for oral use [Link]
Drug created at May 20, 2019 14:46 / Updated at March 29, 2024 06:25