Chang Jae H, Ly Justin, Plise Emile, Zhang Xiaolin, Messick Kirsten, Wright Matthew, Cheong Jonathan
Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California.
Drug Metab Dispos. 2014 Jun;42(6):1067-73. doi: 10.1124/dmd.114.057968. Epub 2014 Mar 26.
Atorvastatin is eliminated by CYP3A4 which follows carrier-mediated uptake into hepatocytes by OATP1B1, OATP1B3, and OATP2B1. Multiple clinical studies demonstrated that OATP inhibition by rifampin had a greater impact on atorvastatin systemic concentration than itraconazole-mediated CYP3A4 inhibition. If it is assumed that the blood and hepatocyte compartments are differentiated by the concentration gradient that is established by OATPs, and if the rate of uptake into the hepatocyte is rate-determining to the elimination of atorvastatin from the body, then it is hypothesized that blood concentrations may not necessarily reflect liver concentrations. In wild-type mice, rifampin had a greater effect on systemic exposure of atorvastatin than ketoconazole, as the blood area under the blood concentration-time curve increased 7- and 2-fold, respectively. In contrast, liver concentrations were affected more by ketoconazole than by rifampin, as liver levels increased 21- and 4-fold, respectively. Similarly, in Cyp3a knockout animals, 39-fold increases in liver concentrations were observed despite insignificant changes in the blood area under the blood concentration-time curve. Interestingly, blood and liver levels in Oatp1a/b knockout animals were similar to wild types, suggesting that Oatp1a/b knockout may be necessary but not sufficient to completely describe atorvastatin uptake in mice. Data presented in this work indicate that there is a substantial drug interaction when blocking atorvastatin metabolism, but the effects of this interaction are predominantly manifested in the liver and may not be captured when monitoring changes in the systemic circulation. Consequently, there may be a disconnect when trying to relate blood exposure to instances of hepatotoxicity because a pharmacokinetic-toxicity relationship may not be obvious from blood concentrations.
阿托伐他汀通过CYP3A4代谢，而CYP3A4通过有机阴离子转运多肽1B1（OATP1B1）、有机阴离子转运多肽1B3（OATP1B3）和有机阴离子转运多肽2B1（OATP2B1）介导的载体转运进入肝细胞。多项临床研究表明，利福平对OATP的抑制作用对阿托伐他汀全身浓度的影响比对伊曲康唑介导的CYP3A4抑制作用更大。如果假设血液和肝细胞腔室由OATP建立的浓度梯度区分，并且如果进入肝细胞的摄取速率是阿托伐他汀从体内消除的速率决定因素，那么可以推测血液浓度不一定反映肝脏浓度。在野生型小鼠中，利福平对阿托伐他汀全身暴露的影响比酮康唑更大，因为血药浓度-时间曲线下面积分别增加了7倍和2倍。相比之下，酮康唑对肝脏浓度的影响比利福平更大，因为肝脏水平分别增加了21倍和4倍。同样，在Cyp3a基因敲除动物中，尽管血药浓度-时间曲线下面积变化不显著，但肝脏浓度增加了39倍。有趣的是，Oatp1a/b基因敲除动物的血液和肝脏水平与野生型相似，这表明Oatp1a/b基因敲除可能是必要的，但不足以完全描述小鼠中阿托伐他汀的摄取情况。这项工作中呈现的数据表明，阻断阿托伐他汀代谢时存在显著的药物相互作用，但这种相互作用的影响主要表现在肝脏中，在监测体循环变化时可能无法检测到。因此，在试图将血液暴露与肝毒性实例联系起来时可能存在脱节，因为从血药浓度中可能无法明显看出药代动力学-毒性关系。
