Effects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats.
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.
Zhang
Y
Y
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California, USA.
Hsieh
Y
Y
Izumi
T
T
Lin
E T
ET
Benet
L Z
LZ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001682:Biological Availability; D001692:Biological Transport; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004151:Dipeptides / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D013450:Sulfones; C115125:morpholin- urea-phenylalanyl-homophenylalanyl-vinylsulfone-phenyl; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D007654:Ketoconazole