Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo

Clin Pharmacol Ther. 2008 Jan;83(1):77-85. doi: 10.1038/sj.clpt.6100230. Epub 2007 May 9.


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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adult
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / pharmacokinetics
  • Antifungal Agents / pharmacology*
  • Biotransformation
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Glucuronides / metabolism
  • Humans
  • Itraconazole / administration & dosage
  • Itraconazole / analogs & derivatives*
  • Itraconazole / pharmacokinetics
  • Itraconazole / pharmacology*
  • Liver / drug effects*
  • Liver / enzymology
  • Male
  • Models, Biological


  • Antifungal Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Glucuronides
  • hydroxyitraconazole
  • Itraconazole
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human