PT  - JOURNAL ARTICLE
AU  - Quinney, Sara K.
AU  - Galinsky, Raymond E.
AU  - Jiyamapa-Serna, Vanida A.
AU  - Chen, Yong
AU  - Hamman, Mitchell A.
AU  - Hall, Stephen D.
AU  - Kimura, Robert E.
TI  - Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats
AID  - 10.1124/dmd.108.020644
DP  - 2008 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 1097--1101
VI  - 36
IP  - 6
4099  - http://dmd.aspetjournals.org/content/36/6/1097.short
4100  - http://dmd.aspetjournals.org/content/36/6/1097.full
SO  - Drug Metab Dispos2008 Jun 01; 36
AB  - 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 (CIN,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 CIN,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. The American Society for Pharmacology and Experimental Therapeutics