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Vol. 287, Issue 1, 246-252, October 1998
Department of Biopharmaceutical Sciences, School of Pharmacy,
University of California, San Francisco, California
We investigated the effects of ketoconazole on the oral bioavailability
of morpholine-urea-phenylalanine-homophenylalanine-vinylsulfone-phenyl (K02), a vinylsulfone peptidomimetic cysteine protease inhibitor, and a
P450 3A (CYP3A) and P-glycoprotein dual substrate, in male Sprague-Dawley rats, so as to evaluate the roles of CYP3A and P-gp in
K02 disposition. Male Sprague-Dawley rats (8-10 wk old, n = 3-6) were administered a single dose of K02 (10 mg/kg) i.v. or (30 mg/kg) p.o. with or without a concomitant oral dose
of ketoconazole (20 mg/kg). Blood samples were collected from 2 min to
8 h after administration through a implanted jugular vein cannula. K02 plasma concentrations were determined by liquid chromatography/mass spectrometer/mass spectrometer analysis. Ketoconazole markedly raised
the area under the curve of orally administered K02 from 9.4 ± 4.4 to 102 ± 24 mg · min/liter and decreased K02 oral
plasma clearance from 3810 ± 1620 to 306 ± 60 ml/min/kg.
With concomitant ketoconazole dosing, the changes of AUC of i.v.
administered K02 (from 94 ± 17 to 107 ± 14 mg · min/liter) and clearance (from 110 ± 22 to 95 ± 13 ml/min/kg) were not significant, although K02 oral bioavailability
increased from 2.9 ± 1.4 to 31.0 ± 7.5% (P < .001).
In summary, ketoconazole, a dual inhibitor of CYP3A and P-glycoprotein,
can effectively increase K02 oral bioavailability by inhibiting the
CYP3A/P-gp absorption barrier in the small intestine.
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