Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats

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 ( F H ) 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 F H 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 F H , whereas there was no time delay observed between the change in F H and the OH-ITZ concentrations entering the liver ( C IN,OH-ITZ ). The direct relationship between C IN,OH-ITZ and F H 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 C IN,OH-ITZ versus F H 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 F H of ITZ.