Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs.
To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.
Kuroha
Masanori
M
Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-0054, Japan.
Azumano
Akinori
A
Kuze
Yoji
Y
Shimoda
Minoru
M
Kokue
Eiichi
E
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D008874:Midazolam; D007654:Ketoconazole