Prueksaritanont T, Ma B, Tang C, Meng Y, Assang C, Lu P, Reider P J, Lin J H, Baillie T A
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Br J Clin Pharmacol. 1999 Mar;47(3):291-8. doi: 10.1046/j.1365-2125.1999.00903.x.
To determine the effects of mibefradil on the nletabolism in human liver microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin.
Metabolism of the above five statins (0.5, 5 or 10 microM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and absence of mibefradil (0.1-50 microM).
Mibefradil inhibited, in a concentration-dependent fashion, the metabolism of the four statins (simvastatin, lovastatin, atorvastatin and cerivastatin) known to be substrates for CYP3A. The potency of inhibition was such that the IC50 values (<1 microM) for inhibition of all of the CYP3A substrates fell within the therapeutic plasma concentrations of mibefradil, and was comparable with that of ketoconazole. However, the inhibition by mibefradil, unlike that of ketoconazole, was at least in part mechanism-based. Based on the kinetics of its inhibition of hepatic testosterone 6beta-hydroxylase activity, mibefradil was judged to be a powerful mechanism-based inhibitor of CYP3A4/5, with values for Kinactivation, Ki and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min(-1), 2.3 microM and 1.7, respectively. In contrast to the results with substrates of CYP3A, metabolism of fluvastatin, a substrate of CYP2C8/9, and the hydroxylation of tolbutamide, a functional probe for CYP2C8/9, were not inhibited by mibefradil.
Mibefradil, at therapeutically relevant concentrations, strongly suppressed the metabolism in human liver microsomes of simvastatin, lovastatin, atorvastatin and cerivastatin through its inhibitory effects on CYP3A4/5, while the effects of mibefradil on fluvastatin, a substrate for CYP2C8/9, were minimal in this system. Since mibefradil is a potent mechanism-based inhibitor of CYP3A4/5, it is anticipated that clinically significant drug-drug interactions will likely ensue when mibefradil is coadministered with agents which are cleared primarily by CYP3A-mediated pathways.
确定米贝拉地尔对HMG-CoA还原酶抑制剂辛伐他汀、洛伐他汀、阿托伐他汀、西立伐他汀和氟伐他汀在人肝微粒体制剂中的代谢影响。
在有和没有米贝拉地尔（0.1 - 50μM）存在的情况下，检测上述五种他汀类药物（0.5、5或10μM）以及特定的CYP3A4/5和CYP2C8/9标记底物在人肝微粒体制剂中的代谢情况。
米贝拉地尔以浓度依赖性方式抑制已知为CYP3A底物的四种他汀类药物（辛伐他汀、洛伐他汀、阿托伐他汀和西立伐他汀）的代谢。抑制效力使得抑制所有CYP3A底物的IC50值（<1μM）落在米贝拉地尔的治疗血浆浓度范围内，并且与酮康唑相当。然而，与酮康唑不同，米贝拉地尔的抑制至少部分是基于机制的。基于其对肝睾酮6β-羟化酶活性抑制的动力学，米贝拉地尔被判定为CYP3A4/5的强效基于机制的抑制剂，其失活速率常数（Kinactivation）、抑制常数（Ki）和分配比（每摩尔失活酶代谢的米贝拉地尔摩尔数）分别为0.4 min(-1)、2.3μM和1.7。与CYP3A底物的结果相反，氟伐他汀（CYP2C8/9的底物）的代谢以及甲苯磺丁脲（CYP2C8/9的功能探针）的羟化未被米贝拉地尔抑制。
在治疗相关浓度下，米贝拉地尔通过对CYP3A4/5的抑制作用，强烈抑制人肝微粒体中辛伐他汀、洛伐他汀、阿托伐他汀和西立伐他汀的代谢，而在该系统中米贝拉地尔对氟伐他汀（CYP2C8/9的底物）的影响最小。由于米贝拉地尔是CYP3A4/5的强效基于机制的抑制剂，预计当米贝拉地尔与主要通过CYP3A介导途径清除的药物合用时，可能会发生具有临床意义的药物相互作用。
