Drug-drug interaction of atazanavir on UGT1A1-mediated glucuronidation of molidustat in human.
Basic Clin Pharmacol Toxicol
; 128(3): 511-524, 2021 Mar.
Article
em En
| MEDLINE
| ID: mdl-33232579
ABSTRACT
Molidustat is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl-hydroxylase enhancing the erythropoietin (EPO) response to HIF; it is in clinical development for the treatment of anaemia related to chronic kidney disease. The predominant role of glucuronidation for molidustat clearance (formation of N-glucuronide metabolite M1) and subsequent renal excretion was confirmed in a human mass balance study, with about 85% of the drug being excreted as M1 in urine. The inhibitory effects of 176 drugs and xenobiotics from various compound classes on the UGT-mediated glucuronidation of molidustat in human liver microsomes (HLMs) were investigated. Based on preclinical findings, glucuronidation of molidustat was predominantly mediated by the 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A1. Therefore, atazanavir, which is a potent inhibitor of UGT1A1, was chosen for the evaluation of pharmacokinetics and EPO release following a single oral dose of 25 mg molidustat. Molidustat exposure increased about twofold upon coadministration with atazanavir when considering area under plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (Cmax ). Baseline-corrected increase of EPO was 14% and 34% for Cmax and AUC (calculated over 24 hours), respectively. Coadministration of molidustat and atazanavir was well tolerated.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Triazóis
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Glucuronosiltransferase
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Glucuronídeos
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Sulfato de Atazanavir
Limite:
Adult
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Basic Clin Pharmacol Toxicol
Ano de publicação:
2021
Tipo de documento:
Article