Fujino H, Saito T, Tsunenari Y, Kojima J, Sakaeda T
Tokyo New Drug Research Laboratories I, Kowa Company Ltd, 2-17-43 Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Xenobiotica. 2004 Nov-Dec;34(11-12):961-71. doi: 10.1080/00498250400015319.
To gain a better understanding of the metabolic properties between the open acid and lactone form of HMG-CoA reductase inhibitors (statins), the paper focused primarily on characterizing the metabolic properties of statins. We compared the metabolism of the acid and lactone forms of several statins, including atrovastatin, simvastatin, cerivastatin fluvastatin, pitavastatin and rosuvastatin with respect to metabolic clearance, CYP enzymes involved and drug-drug interactions. A remarkable increase in metabolic clearance was noted for all lactones compared with all acids except for pitavastatin lactone. The metabolic clearances of the atrovastatin, simvastatin, cerivastatin, fluvastatin and rosuvastatin lactones were 73-, 70-, 30-, 7- and 64-fold higher, respectively, than those of the corresponding acids. CYP2Cs were critically involved in the metabolism of cerivastatin, fluvastatin and pitavastatin acids. In contrast, CYP2Cs were not involved in the metabolism of the corresponding lactones and CYP3A4 was mainly involved. Moreover, a substantial difference in the metabolic inhibition of statins was found between acids and lactones. Overall, the study demonstrates that CYP-mediated metabolism of lactones is also a common metabolic pathway for statins and that the CYP3A4-mediated metabolism of the lactone forms clearly will need to be taken into account in assessing mechanistic aspects of drug-drug interaction involving statins.
为了更好地理解HMG - CoA还原酶抑制剂（他汀类药物）的游离酸形式和内酯形式之间的代谢特性，该论文主要聚焦于他汀类药物代谢特性的表征。我们比较了几种他汀类药物的酸形式和内酯形式的代谢情况，包括阿托伐他汀、辛伐他汀、西立伐他汀、氟伐他汀、匹伐他汀和瑞舒伐他汀，涉及代谢清除率、参与的CYP酶以及药物 - 药物相互作用。除匹伐他汀内酯外，与所有酸形式相比，所有内酯形式的代谢清除率均显著增加。阿托伐他汀、辛伐他汀、西立伐他汀、氟伐他汀和瑞舒伐他汀内酯的代谢清除率分别比相应酸形式高73倍、70倍、30倍、7倍和64倍。CYP2Cs关键参与西立伐他汀、氟伐他汀和匹伐他汀酸的代谢。相比之下，CYP2Cs不参与相应内酯的代谢，主要参与的是CYP3A4。此外，在酸形式和内酯形式的他汀类药物代谢抑制方面发现了显著差异。总体而言，该研究表明，内酯的CYP介导代谢也是他汀类药物的常见代谢途径，并且在评估涉及他汀类药物的药物 - 药物相互作用的机制方面，显然需要考虑内酯形式的CYP3A4介导的代谢。
