Inhibitory effects of ketoconazole, cimetidine and erythromycin on hepatic CYP3A activities in cats.
Inhibitory effects of ketoconazole (KTZ), cimetidine (CIM), and erythromycin (ERY) were examined on CYP3A activities. Midazolam 1'- and 4-hydroxylation (MDZ1'H and MDZ4H) were used to determine CYP3A activities in hepatic microsomes obtained from cats (n=4). The results showed that, all the examined drugs inhibited the reactions in a noncompetitive manner. The inhibitory constants (Ki) of KTZ were 2.80 +/- 0.70 and 115 +/- 28 microM for MDZ1'H and MDZ4H, respectively. Those of CIM were 3.13 and 3.27 mM and of ERY were 3.14 and 6.41 mM for MDZ1'H and MDZ4H, respectively. Mechanism-based inhibition was also examined in this study. KTZ significantly reduced MDZ reactions in a time-dependent manner; while CIM and ERY did not. Also, the effects of KTZ and CIM on the pharmacokinetics of quinidine (QUN) were studied. KTZ or CIM (10 mg/kg/day, for one week) was given orally to cats (n=5). QUN (2 mg/kg, i. v.) was injected 2 hr after the last dose of KTZ or CIM. The analysis of the obtained pharmacokinetic parameters showed that, KTZ significantly reduced total body clearance of QUN by 35%, while CIM did not. These results suggest that, KTZ inhibits CYP3A activities (both in vitro and in vivo), but CIM does not. In clinical practice, therefore, KTZ may result in inhibition based drug-drug interaction with CYP3A substrates in cat patients, whereas CIM and ERY are unlikely to lead to interaction involving CYP3A substrates.
Shah
Syed Sher
SS
Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
Sasaki
Kazuaki
K
Hayashi
Yuhei
Y
Motoyama
Seiko
S
Helmi
Abdou Rania
AR
Khalil
Waleed Fathy
WF
Shimoda
Minoru
M
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D019540:Area Under Curve; D002415:Cats; D002927:Cimetidine / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004917:Erythromycin / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology*; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D004917:Erythromycin; D002927:Cimetidine; D008874:Midazolam; D007654:Ketoconazole