Stereochemical aspects of itraconazole metabolism in vitro and in vivo.

Journal Article (Clinical Trial;Journal Article)

Itraconazole (ITZ) has three chiral centers and is administered clinically as a mixture of four stereoisomers. This study evaluated stereoselectivity in ITZ metabolism. In vitro experiments were carried out using heterologously expressed CYP3A4. Only (2R,4S,2'R)-ITZ and (2R,4S,2'S)-ITZ were metabolized by CYP3A4 to hydroxy-ITZ, keto-ITZ, and N-desalkyl-ITZ. When (2S,4R,2'R)-ITZ or (2S,4R,2'S)-ITZ was incubated with CYP3A4, neither metabolites nor substrate depletion were detected. Despite these differences in metabolism, all four ITZ stereoisomers induced a type II binding spectrum with CYP3A4, characteristic of coordination of the triazole nitrogen to the heme iron (K(s) 2.2-10.6 nM). All four stereoisomers of ITZ inhibited the CYP3A4-catalyzed hydroxylation of midazolam with high affinity (IC(50) 3.7-14.8 nM). Stereochemical aspects of ITZ pharmacokinetics were evaluated in six healthy volunteers after single and multiple oral doses. In vivo, after a single dose, ITZ disposition was stereoselective, with a 3-fold difference in C(max) and a 9-fold difference in C(min) between the (2R,4S)-ITZ and the (2S,4R)-ITZ pairs of diastereomers, with the latter reaching higher concentrations. Secondary and tertiary ITZ metabolites (keto-ITZ and N-desalkyl-ITZ) detected in plasma were of the (2R,4S) stereochemistry. After multiple doses of ITZ, the difference in C(max) and C(min) decreased to 1.5- and 3.8-fold, respectively. The initial difference between the stereoisomeric pairs was most likely due to stereoselective metabolism by CYP3A4, including stereoselective first-pass metabolism as well as stereoselective elimination. However, stereoselective elimination was diminished after multiple dosing, presumably as a result of CYP3A4 autoinhibition. In conclusion, the metabolism of ITZ is highly stereoselective in vitro and in vivo.

Full Text

Duke Authors

Cited Authors

  • Kunze, KL; Nelson, WL; Kharasch, ED; Thummel, KE; Isoherranen, N

Published Date

  • April 2006

Published In

Volume / Issue

  • 34 / 4

Start / End Page

  • 583 - 590

PubMed ID

  • 16415110

International Standard Serial Number (ISSN)

  • 0090-9556

Digital Object Identifier (DOI)

  • 10.1124/dmd.105.008508


  • eng

Conference Location

  • United States