Journal of Veterinary Medical Science
Online ISSN : 1347-7439
Print ISSN : 0916-7250
ISSN-L : 0916-7250
Pharmacology
Inhibitory Effects of Ketoconazole, Cimetidine and Erythromycin on Hepatic CYP3A Activities in Cats
Syed Sher SHAHKazuaki SASAKIYuhei HAYASHISeiko MOTOYAMAAbdou Rania HELMIWaleed Fathy KHALILMinoru SHIMODA
Author information
JOURNAL FREE ACCESS

2009 Volume 71 Issue 9 Pages 1151-1159

Details
Abstract

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 μM 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.

Content from these authors
© 2009 by the Japanese Society of Veterinary Science

この記事はクリエイティブ・コモンズ [表示 - 非営利 - 改変禁止 4.0 国際]ライセンスの下に提供されています。
https://creativecommons.org/licenses/by-nc-nd/4.0/deed.ja
Previous article Next article
feedback
Top