Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Clin Pharmacol Ther. 2011 Oct;90(4):575-81. doi: 10.1038/clpt.2011.142. Epub 2011 Aug 10.
Clearance of atorvastatin occurs through hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative importance of OATPs and CYP3A4 in the hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe substrates for OATPs (pravastatin) and CYP3A4 (midazolam) was orally administered to eight healthy volunteers. The pharmacokinetics of this cocktail was observed at baseline, after an oral dose of 600 mg rifampicin (an inhibitor of OATPs), and after an intravenous dose of 200 mg itraconazole (a CYP3A4 inhibitor). Rifampicin increased the pravastatin dose-normalized area under the plasma concentration-time curve (AUC) (4.6-fold), and itraconazole significantly increased the midazolam dose-normalized AUC (1.7-fold). The atorvastatin dose-normalized AUC increased 12-fold when coadministered with rifampicin but did not change when coadministered with itraconazole. These results indicate that hepatic uptake via OATPs makes the dominant contribution to the hepatic elimination of atorvastatin at a subtherapeutic microdose.
阿托伐他汀的清除主要通过有机阴离子转运多肽（OATPs）摄取到肝脏中，并随后由细胞色素 P450（CYP）3A4 代谢。为了证明 OATPs 和 CYP3A4 在阿托伐他汀体内肝脏消除中的相对重要性，进行了一项临床盒式微剂量研究。将由阿托伐他汀微剂量和 OATP（普伐他汀）和 CYP3A4（咪达唑仑）探针底物组成的混合物口服给予 8 名健康志愿者。在基线、口服 600 毫克利福平（OATPs 抑制剂）后和静脉注射 200 毫克伊曲康唑（CYP3A4 抑制剂）后观察该混合物的药代动力学。利福平使普伐他汀剂量归一化的血浆浓度-时间曲线下面积（AUC）增加了 4.6 倍（4.6 倍），伊曲康唑显著增加了咪达唑仑剂量归一化的 AUC（1.7 倍）。当与利福平合用时，阿托伐他汀剂量归一化的 AUC 增加了 12 倍，但当与伊曲康唑合用时没有变化。这些结果表明，在亚治疗微剂量下，OATPs 通过肝脏摄取对阿托伐他汀的肝脏消除做出了主要贡献。
