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 m...
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Published in | Drug metabolism and disposition Vol. 36; no. 6; pp. 1097 - 1101 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.06.2008
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Subjects | |
Online Access | Get full text |
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Summary: | 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 32:1121â1131, 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.108.020644 |