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Drug Metabolism and Disposition Fast Forward
First published on March 13, 2008; DOI: 10.1124/dmd.108.020644

0090-9556/08/3606-1097-1101$20.00
DMD 36:1097-1101, 2008

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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. Hall1, and Robert E. Kimura

Division of Clinical Pharmacology, Department of Medicine, Indiana University, Indianapolis, Indiana (S.K.Q., R.E.G., M.A.H., S.D.H.); Department of Industrial & Physical Pharmacy, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana (R.E.G.); and Section of Neonatology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois (V.A.J.-S., Y.C., R.E.K.)

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.

Address correspondence to: Dr. R. E. Galinsky, Division of Clinical Pharmacology, Room W7123 Myers, Wishard Memorial Hospital, 1001 West 10th Street, Indianapolis, IN 46202. E-mail: rgalinsk{at}iupui.edu






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