Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo.

Journal Article (Clinical Trial;Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Templeton, IE; Thummel, KE; Kharasch, ED; Kunze, KL; Hoffer, C; Nelson, WL; Isoherranen, N

Published Date

  • January 2008

Published In

Volume / Issue

  • 83 / 1

Start / End Page

  • 77 - 85

PubMed ID

  • 17495874

Pubmed Central ID

  • PMC3488349

Electronic International Standard Serial Number (EISSN)

  • 1532-6535

Digital Object Identifier (DOI)

  • 10.1038/sj.clpt.6100230


  • eng

Conference Location

  • United States