Shah Syed Sher, Sasaki Kazuaki, Hayashi Yuhei, Motoyama Seiko, Helmi Abdou Rania, Khalil Waleed Fathy, Shimoda Minoru
Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
J Vet Med Sci. 2009 Sep;71(9):1151-9. doi: 10.1292/jvms.71.1151.
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.
研究了酮康唑（KTZ）、西咪替丁（CIM）和红霉素（ERY）对CYP3A活性的抑制作用。采用咪达唑仑1'-羟化和4-羟化反应（MDZ1'H和MDZ4H）来测定从猫（n = 4）获得的肝微粒体中的CYP3A活性。结果表明，所有受试药物均以非竞争性方式抑制反应。KTZ对MDZ1'H和MDZ4H的抑制常数（Ki）分别为2.80±0.70和115±28μM。CIM对MDZ1'H和MDZ4H的抑制常数分别为3.13和3.27 mM，ERY对MDZ1'H和MDZ4H的抑制常数分别为3.14和6.41 mM。本研究还考察了基于机制的抑制作用。KTZ以时间依赖性方式显著降低MDZ反应；而CIM和ERY则没有。此外，研究了KTZ和CIM对奎尼丁（QUN）药代动力学的影响。给猫（n = 5）口服KTZ或CIM（10 mg/kg/天，持续一周）。在最后一剂KTZ或CIM后2小时静脉注射QUN（2 mg/kg）。对获得的药代动力学参数分析表明，KTZ显著降低QUN的全身清除率35%，而CIM则没有。这些结果表明，KTZ抑制CYP3A活性（体外和体内均如此），但CIM不抑制。因此，在临床实践中，KTZ可能导致猫患者中与CYP3A底物发生基于抑制的药物相互作用，而CIM和ERY不太可能导致涉及CYP3A底物的相互作用。
