Wang Jun-Sheng, Neuvonen Mikko, Wen Xia, Backman Janne T, Neuvonen Pertti J
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Drug Metab Dispos. 2002 Dec;30(12):1352-6. doi: 10.1124/dmd.30.12.1352.
To explore the mechanism of the interaction between gemfibrozil and cerivastatin, the enzyme mapping of the oxidative metabolism of cerivastatin and the effect of gemfibrozil on cerivastatin metabolism were studied using human liver microsomes and expressed cytochrome p450 (p450) CYP2C8 and 3A4 isoforms. Based on studies with isoform-selective chemical inhibitors and expressed enzymes, CYP2C8 and CYP3A4 were equally important in the formation of desmethylcerivastatin (M-1), whereas the formation of the quantitatively most important hydroxy metabolite (M-23) was predominantly mediated via CYP2C8; other p450 isoforms played a negligible role. In human liver microsomes, gemfibrozil markedly inhibited M-23 formation, with a K(i) (IC(50)) value of 69 (95) micro M, whereas inhibition of M-1 formation was weaker with a K(i) (IC(50)) value of 273 (>250) micro M. The inhibitory effect of gemfibrozil was attributable to inhibition of CYP2C8 rather than CYP3A4, as evidenced by potent inhibition of the formation of M-23 (IC(50) = 68 micro M) and M-1 (IC(50) = 78 micro M) in recombinant CYP2C8 but not in recombinant CYP3A4. Additionally, gemfibrozil inhibited paclitaxel 6 alpha-hydroxylation [K(i) (IC(50)) = 75 micro M (91 micro M)], a CYP2C8 marker reaction, but did not inhibit testosterone 6 beta-hydroxylation (CYP3A4). The present in vitro findings suggest that inhibition of CYP2C8 activity by gemfibrozil at least partially explains the interaction between gemfibrozil and cerivastatin. The formation of M-23 acid from cerivastatin is mediated mainly by CYP2C8 and thus may be a suitable CYP2C8 probe reaction. Inhibition of CYP2C8-mediated metabolism by gemfibrozil warrants further in vivo exploration.
为探究吉非贝齐与西立伐他汀之间相互作用的机制，利用人肝微粒体以及表达的细胞色素P450（P450）CYP2C8和3A4同工型，研究了西立伐他汀氧化代谢的酶谱分析以及吉非贝齐对西立伐他汀代谢的影响。基于同工型选择性化学抑制剂和表达酶的研究，CYP2C8和CYP3A4在去甲基西立伐他汀（M-1）的形成中同等重要，而在数量上最重要的羟基代谢物（M-23）的形成主要通过CYP2C8介导；其他P450同工型起的作用可忽略不计。在人肝微粒体中，吉非贝齐显著抑制M-23的形成，K(i)（IC(50)）值为69（95）μM，而对M-1形成的抑制较弱，K(i)（IC(50)）值为273（>250）μM。吉非贝齐的抑制作用归因于对CYP2C8的抑制而非CYP3A4，重组CYP2C8中M-23（IC(50) = 68 μM）和M-1（IC(50) = 78 μM）形成受到有效抑制，而重组CYP3A4中未受抑制，这证明了这一点。此外，吉非贝齐抑制紫杉醇6α-羟基化[K(i)（IC(50)）= 75 μM（91 μM）]，这是一种CYP2C8标记反应，但不抑制睾酮6β-羟基化（CYP3A4）。目前的体外研究结果表明，吉非贝齐对CYP2C8活性的抑制至少部分解释了吉非贝齐与西立伐他汀之间的相互作用。西立伐他汀形成M-23酸主要由CYP2C8介导，因此可能是一种合适的CYP2C8探针反应。吉非贝齐对CYP2C8介导的代谢的抑制值得进一步进行体内研究。
