Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension.
Article Details
- CitationCopy to clipboard
Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C
Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension.
J Clin Pharmacol. 2012 Dec;52(12):1784-805. doi: 10.1177/0091270011423662. Epub 2011 Dec 28.
- PubMed ID
- 22205719 [ View in PubMed]
- Abstract
The authors review the basic pharmacology and potential for adverse drug-drug interactions (DDIs) of bosentan and ambrisentan, the 2 endothelin receptor antagonists currently approved for pulmonary arterial hypertension (PAH) treatment. Bosentan, an endothelin (ET) receptor-type ET(A) and ET(B) antagonist, is metabolized to active metabolites by and an inducer of cytochrome P450 (CYP)2C9 and CYP3A. Ambrisentan, a selective ET(A) receptor antagonist, is metabolized primarily by uridine 5'diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S and, to a lesser extent, by CYP3A and CYP2C19. Drug interactions observed with bosentan DDI studies have demonstrated a potential for significant clinical implications during PAH management: bosentan is contraindicated with cyclosporine A and glyburide, and additional monitoring/dose adjustments are required when coadministered with hormonal contraceptives, simvastatin, lopinavir/ritonavir, and rifampicin. As bosentan carries a boxed warning regarding risks of liver injury and showed dose-dependant increases in serum aminotransferase abnormalities, drug interactions that increase bosentan exposure are of particular clinical concern. Ambrisentan DDI studies performed to date have shown only one clinically relevant DDI, an interaction with cyclosporine A that requires ambrisentan dose reduction. As the treatment of PAH moves toward multimodal combination therapy, scrutiny should be placed on ensuring that drug combinations achieve maximal clinical benefit while minimizing side effects.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Ambrisentan Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Ambrisentan Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Ambrisentan UDP-glucuronosyltransferase 1-3 Protein Humans UnknownSubstrateDetails Ambrisentan UDP-glucuronosyltransferase 1-9 Protein Humans UnknownSubstrateDetails Ambrisentan UDP-glucuronosyltransferase 2B7 Protein Humans UnknownSubstrateDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Ambrisentan P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Ambrisentan Solute carrier organic anion transporter family member 1B1 Protein Humans UnknownSubstrateDetails Ambrisentan Solute carrier organic anion transporter family member 1B3 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details Details Details
