PT  - JOURNAL ARTICLE
AU  - Kunze, Kent L.
AU  - Nelson, Wendel L.
AU  - Kharasch, Evan D.
AU  - Thummel, Kenneth E.
AU  - Isoherranen, Nina
TI  - STEREOCHEMICAL ASPECTS OF ITRACONAZOLE METABOLISM IN VITRO AND IN VIVO
AID  - 10.1124/dmd.105.008508
DP  - 2006 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 583--590
VI  - 34
IP  - 4
4099  - http://dmd.aspetjournals.org/content/34/4/583.short
4100  - http://dmd.aspetjournals.org/content/34/4/583.full
SO  - Drug Metab Dispos2006 Apr 01; 34
AB  - 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 (Ks 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 after single and multiple oral doses. In vivo, after a single dose, ITZ disposition was stereoselective, with a 3-fold difference in Cmax and a 9-fold difference in Cmin 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 Cmax and Cmin 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. The American Society for Pharmacology and Experimental Therapeutics