Prueksaritanont Thomayant, Tang Cuyue, Qiu Yue, Mu Lillian, Subramanian Raju, Lin Jiunn H
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Drug Metab Dispos. 2002 Nov;30(11):1280-7. doi: 10.1124/dmd.30.11.1280.
This study investigated the metabolic interaction between fibrates and statin hydroxy acids in human hepatocytes. Gemfibrozil (GFZ) modestly affected the formation of beta-oxidative products and CYP3A4-mediated oxidative metabolites of simvastatin hydroxy acid (SVA) but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of a beta-oxidation product (IC(50) approximately 50 and 15 microM, respectively). In contrast, fenofibrate had a minimal effect on all the metabolic pathways of SVA. GFZ also significantly inhibited (IC(50) approximately 50-60 microM) the oxidation of cerivastatin (CVA) and rosuvastatin (RVA), but not of atorvastatin (AVA), while effectively decreasing (IC(50) approximately 30 to 60 microM) the lactonization of all three statins. As was observed previously with other statin hydroxy acids, RVA underwent significant glucuronidation to form an acyl glucuronide conjugate and lactonization to form RVA lactone in human liver microsomes and by UGT 1A1 and 1A3. While GFZ is not an inhibitor of CYP3A4, it is a competitive inhibitor (K(i) = 87 microM) of CYP2C8, a major catalyzing enzyme for CVA oxidation. These results suggest that 1) the pharmacokinetic interaction observed between GFZ and statins was not likely mediated by the inhibitory effect of GFZ on the beta-oxidation, but rather by its effect primarily on the glucuronidation and non-CYP3A-mediated oxidation of statin hydroxy acids, and 2) there is a potential difference between fibrates in their ability to affect the pharmacokinetics of statins, and among statins in their susceptibility to metabolic interactions with GFZ in humans.
本研究调查了贝特类药物与他汀类羟酸在人肝细胞中的代谢相互作用。吉非贝齐（GFZ）对辛伐他汀羟酸（SVA）的β-氧化产物形成及CYP3A4介导的氧化代谢产物有适度影响，但显著抑制SVA的葡萄糖醛酸化介导的内酯化及一种β-氧化产物的葡萄糖醛酸化（IC50分别约为50和15微摩尔）。相比之下，非诺贝特对SVA的所有代谢途径影响极小。GFZ还显著抑制（IC50约为50 - 60微摩尔）西立伐他汀（CVA）和瑞舒伐他汀（RVA）的氧化，但不抑制阿托伐他汀（AVA）的氧化，同时有效降低（IC50约为30至60微摩尔）所有三种他汀类药物的内酯化。如先前在其他他汀类羟酸中所观察到的，RVA在人肝微粒体中以及通过UGT 1A1和1A3进行显著的葡萄糖醛酸化以形成酰基葡萄糖醛酸共轭物，并进行内酯化以形成RVA内酯。虽然GFZ不是CYP3A4的抑制剂，但它是CYP2C8的竞争性抑制剂（Ki = 87微摩尔），CYP2C8是CVA氧化的主要催化酶。这些结果表明：1）GFZ与他汀类药物之间观察到的药代动力学相互作用不太可能由GFZ对β-氧化的抑制作用介导，而主要是由其对他汀类羟酸的葡萄糖醛酸化和非CYP3A介导的氧化的影响介导；2）贝特类药物在影响他汀类药物药代动力学的能力方面存在潜在差异，并且在他汀类药物对人类中与GFZ代谢相互作用的敏感性方面也存在差异。
