Polasek Thomas M, Elliot David J, Lewis Benjamin C, Miners John O
Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Bedford Park, Adelaide, South Australia 5042, Australia.
J Pharmacol Exp Ther. 2004 Dec;311(3):996-1007. doi: 10.1124/jpet.104.071803. Epub 2004 Aug 10.
Studies were conducted to evaluate the potential mechanism-based inactivation of recombinant and human liver microsomal CYP2C8 by clinically used drugs. Several tricyclic antidepressants, calcium channel blockers, monoamine oxidase inhibitors, and various other known CYP3A4 inhibitors exhibited greater inhibition of CYP2C8 (paclitaxel 6alpha-hydroxylation) following preincubation, consistent with mechanism-based inactivation. Inactivation of recombinant CYP2C8 by phenelzine, amiodarone, verapamil, nortriptyline, fluoxetine, and isoniazid was of the pseudo-first order type and was characterized by respective inactivation kinetic constants (KI and kinact) of 1.2 microM and 0.243 min(-1), 1.5 microM and 0.079 min(-1), 17.5 microM and 0.065 min(-1), 49.9 microM and 0.036 min(-1), 294 microM and 0.083 min(-1), and 374 microM and 0.042 min(-1). Spectral scanning of recombinant CYP2C8 demonstrated the formation of metabolite-intermediate complexes with verapamil, nortriptyline, fluoxetine, and isoniazid, but not amiodarone. In contrast, inactivation by phenelzine resulted from heme destruction by free radicals. Studies with human liver microsomes (HLMs) revealed that nortriptyline, verapamil, and fluoxetine were not mechanism-based inactivators (MBIs) of CYP2C8. Simultaneous inactivation of CYP2C8 and CYP3A4 (paclitaxel 3'-phenyl-hydroxylation) was observed using amiodarone, isoniazid, and phenelzine with the efficiency of inactivation greater for the CYP3A4 pathway. With the exception of phenelzine, glutathione and superoxide dismutase failed to protect CYP2C8 (recombinant and HLMs) or CYP3A4 from inactivation by MBIs. However, the alternate CYP2C8 substrate, torsemide, prevented CYP2C8 inactivation in all cases. These data are consistent with mechanism-based inactivation of CYP2C8 by a range of commonly prescribed drugs, several of which have been implicated in clinically important drug-drug interactions.
开展了多项研究，以评估临床使用的药物对重组型和人肝微粒体CYP2C8基于潜在机制的失活作用。几种三环类抗抑郁药、钙通道阻滞剂、单胺氧化酶抑制剂以及各种其他已知的CYP3A4抑制剂在预孵育后对CYP2C8（紫杉醇6α-羟基化）表现出更强的抑制作用，这与基于机制的失活作用一致。苯乙肼、胺碘酮、维拉帕米、去甲替林、氟西汀和异烟肼对重组型CYP2C8的失活属于准一级类型，其各自的失活动力学常数（KI和kinact）分别为1.2微摩尔和0.243分钟-1、1.5微摩尔和0.079分钟-1、17.5微摩尔和0.065分钟-1、49.9微摩尔和0.036分钟-1、294微摩尔和0.083分钟-1，以及374微摩尔和0.042分钟-1。重组型CYP2C8的光谱扫描显示，其与维拉帕米、去甲替林、氟西汀和异烟肼形成了代谢物-中间体复合物，但与胺碘酮未形成。相比之下，苯乙肼导致的失活是由自由基破坏血红素引起的。用人肝微粒体（HLMs）进行的研究表明，去甲替林、维拉帕米和氟西汀并非CYP2C8的基于机制的失活剂（MBIs）。使用胺碘酮、异烟肼和苯乙肼时，观察到CYP2C8和CYP3A4（紫杉醇3'-苯基-羟基化）同时失活，且CYP3A4途径的失活效率更高。除苯乙肼外，谷胱甘肽和超氧化物歧化酶无法保护CYP2C8（重组型和HLMs）或CYP3A4免受MBIs的失活作用。然而，替代的CYP2C8底物托拉塞米在所有情况下都能防止CYP2C8失活。这些数据与一系列常用处方药对CYP2C8基于机制的失活作用一致，其中几种药物已涉及具有临床重要意义的药物相互作用。
