Sara K. Quinney

School of Medicine, Obstetrics & Gynecology

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Hydroxyitraconazole, formed during intestinal first-pass metabolism of itraconazole, controls the time course of hepatic CYP3A inhibition and the bioavailability of itraconazole in rats

Sara K. Quinney; Raymond E. Galinsky; Vanida A. Jiyamapa-Serna; Yong Chen; Mitchell A. Hamman; Stephen D. Hall; Robert E. Kimura (Profiled Author: Sara K. Quinney)

Drug Metabolism and Disposition. 2008;36(6):1097-1101.

Itraconazole (ITZ) is a substrate of CYP3A and both ITZ and hydroxyitraconazole (OH-ITZ), a major metabolite formed by CYP3A, are potent inhibitors of CYP3A. The concentration- and time-dependent changes in the hepatic availability (FH) of ITZ were evaluated in rats after oral doses of 5 and 40 mg/kg. Simultaneous blood samples were obtained from the aorta, portal vein, and hepatic vein for 24 h following duodenal ITZ administration, and concentrations of ITZ and OH-ITZ determined by LC/MS. During the absorption phase, the FH of ITZ increased from 0.2 to 1.0, reflecting the time course of hepatic CYP3A inhibition. A counterclockwise hysteresis was observed between ITZ concentrations entering the liver (C IN,ITZ) and FH, whereas there was no time delay observed between the change in FH and the OH-ITZ concentrations entering the liver (CIN,OH-ITZ). The direct relationship between C IN,OH-ITZ and FH suggested that OH-ITZ was mainly responsible for the inhibition of CYP3A. A positive portal venous-aortic gradient for OH-ITZ was measured after duodenal administration of ITZ, indicating intestinal formation of OH-ITZ. The in vivo Ki for OH-ITZ (38 ± 3 nM) was estimated from CIN,OH-ITZ versus FH of ITZ, and is similar to values obtained from inhibition of midazolam hydroxylation in CYP3A4 supersomes (Drug Metab Dispos 32:1121-1131, 2004). The data suggest that OH-ITZ, formed by intestinal CYP3A, controls the time course of hepatic CYP3A inhibition and is mainly responsible for the observed increase in FH of ITZ. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

PMID: 18339815    

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