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National Institute of Environmental Health Sciences

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Publication Detail

Title: Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo.

Authors: Templeton, I E; Thummel, K E; Kharasch, E D; Kunze, K L; Hoffer, C; Nelson, W L; Isoherranen, N

Published In Clin Pharmacol Ther, (2008 Jan)

Abstract: Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

PubMed ID: 17495874 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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