Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, The Netherlands.
Eur J Pharm Sci. 2011 Nov 20;44(4):487-96. doi: 10.1016/j.ejps.2011.09.009. Epub 2011 Sep 16.
It has been reported that polymorphisms in the organic anion transporting polypeptide 1B1 (OATP1B1, SLCO1B1) result in decreased hepatic uptake of simvastatin carboxy acid, the active metabolite of simvastatin. This is not the case for fluvastatin and it has been hypothesized that for this drug other hepatic uptake pathways exist. Here, we studied whether Na(+)-dependent taurocholate co-transporting polypeptide (NTCP, SLC10A1) can be an alternative hepatic uptake route for fluvastatin. Chinese Hamster Ovary cells transfected with human NTCP (CHO-NTCP) were used to investigate the inhibitory effect of fluvastatin and other statins on [(3)H]-taurocholic acid uptake ([(3)H]-TCA). Statin uptake by CHO-NTCP and cryopreserved human hepatocytes was assessed via LC-MS/MS. Fluvastatin appeared to be a potent and competitive inhibitor of [(3)H]-TCA uptake (IC(50) of 40μM), pointing to an interaction at the level of the bile acid binding pocket of NTCP. The inhibitory action of other statins was also studied, which revealed that statin inhibitory potency increased with molecular descriptors of lipophilicity: calculated logP (r(2)=0.82, p=0.034), logD(7.4) (r(2)=0.77, p=0.0001). Studies in CHO-NTCP cells showed that fluvastatin was indeed an NTCP substrate (K(m) 250±30μM, V(max) 1340±50ng/mg total cell protein/min). However, subsequent studies revealed that at clinically relevant plasma concentrations, NTCP contributed minimally to overall accumulation in human hepatocytes. In conclusion, fluvastatin interacts with NTCP at the level of the bile acid binding pocket and is an NTCP substrate. However, under normal conditions, NTCP-mediated uptake of this drug seems not to be a significant hepatocellular uptake pathway.
据报道，有机阴离子转运多肽 1B1（OATP1B1，SLCO1B1）的多态性导致辛伐他汀羧酸（辛伐他汀的活性代谢物）的肝摄取减少。对于氟伐他汀则不是这样，人们假设对于这种药物，存在其他的肝摄取途径。在这里，我们研究了钠离子依赖性牛磺胆酸共转运蛋白（NTCP，SLC10A1）是否可以作为氟伐他汀的替代肝摄取途径。用人 NTCP（CHO-NTCP）转染的中国仓鼠卵巢细胞（CHO）用于研究氟伐他汀和其他他汀类药物对[3H]-牛磺胆酸摄取的抑制作用[3H]-TCA）。通过 LC-MS/MS 评估他汀类药物在 CHO-NTCP 和冷冻保存的人肝细胞中的摄取。氟伐他汀似乎是[3H]-TCA 摄取的有效和竞争性抑制剂（IC50 为 40μM），表明在 NTCP 的胆汁酸结合口袋水平存在相互作用。还研究了其他他汀类药物的抑制作用，结果表明他汀类药物的抑制效力随着脂溶性的分子描述符而增加：计算的 logP（r2=0.82，p=0.034），logD（7.4）（r2=0.77，p=0.0001）。在 CHO-NTCP 细胞中的研究表明，氟伐他汀确实是 NTCP 的底物（K(m)250±30μM，V(max)1340±50ng/mg 总细胞蛋白/分钟）。然而，随后的研究表明，在临床相关的血浆浓度下，NTCP 对人肝细胞中的总体积累贡献最小。总之，氟伐他汀在胆汁酸结合口袋水平与 NTCP 相互作用，是 NTCP 的底物。然而，在正常情况下，NTCP 介导的摄取这种药物似乎不是一个重要的肝细胞摄取途径。
