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Title: Stereochemical aspects of itraconazole metabolism in vitro and in vivo.

Authors: Kunze, Kent L; Nelson, Wendel L; Kharasch, Evan D; Thummel, Kenneth E; Isoherranen, Nina

Published In Drug Metab Dispos, (2006 Apr)

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 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.

PubMed ID: 16415110 Exiting the NIEHS site

MeSH Terms: Adolescent; Adult; Antifungal Agents/chemistry; Antifungal Agents/pharmacokinetics*; Antifungal Agents/pharmacology; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System/antagonists & inhibitors; Cytochrome P-450 Enzyme System/genetics; Cytochrome P-450 Enzyme System/metabolism; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacokinetics*; Enzyme Inhibitors/pharmacology; Female; Humans; Itraconazole/chemistry; Itraconazole/pharmacokinetics*; Itraconazole/pharmacology; Male; Microsomes, Liver/enzymology; Microsomes, Liver/metabolism; Recombinant Proteins/metabolism; Stereoisomerism

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