Received for publication November 28, 2005.
Revised January 11, 2006.
Accepted for publication January 12, 2006.

Stereochemical Aspects of Itraconazole Metabolism in vitro and in vivo

Abstract

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 co-ordination of the triazole nitrogen to the heme iron (K_d 2.2-10.6 nM). All four stereoisomers of ITZ inhibited the CYP3A4-catalyzed hydroxylation of midazolam with high affinity (IC₅₀ 3.7-14.8 nM). Stereochemical aspects of ITZ pharmacokinetics were evaluated in six healthy volunteers following single and multiple oral doses. In vivo, after single dose ITZ disposition was stereoselective, with a 3-fold difference in C_max and 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 auto-inhibition. In conclusion, the metabolism of ITZ is highly stereoselective in vitro and in vivo.

Key words: CYP inhibition, CYP3A, drug disposition, drug interactions, drug-drug interactions, enzyme kinetics, human CYP enzymes, human pharmacokinetics, metabolite kinetics, pharmacokinetics

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