Received for publication January 28, 2008.
Revised March 11, 2008.
Accepted for publication March 12, 2008.

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

Abstract

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 hours 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 counter-clockwise 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 vs. F_H of ITZ, and is similar to values obtained from inhibition of midazolam hydroxylation in CYP3A4 supersomes (Isoherranen et al., 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.

Key words: bioavailability, cytochrome P450, drug disposition, first-pass metabolism, liver physiology/models