有机阴离子转运多肽(OATP)2B1被认为是一种新兴的药物转运蛋白,在药代动力学相关器官如肝脏中表达。小肠,还有肾.尽管它与各种底物药物相互作用,对其体内相关性的理解仍然有限。在这项研究中,我们首先使用瞬时转染的HeLa细胞验证了阿托伐他汀与大鼠OATP2B1的相互作用。此外,我们表征了rSlco2b1敲除和SLCO2B1敲入大鼠的mRNA,蛋白质表达,OATP2B1在肝脏中的定位,小肠,还有肾.转运体在肝脏中表达最高,其次是小肠。在人源化大鼠中,人OATP2B1位于肝细胞的正弦膜上。在野生型和人源化大鼠的肠上皮细胞中,在腔膜中检测到转运蛋白,绝大多数位于根尖下。随后,我们评估了阿托伐他汀在男性野性pe中的药代动力学,rSlco2b1-淘汰赛,单剂量给药(口服和静脉内)后,SLCO2B1敲入大鼠。研究大鼠OATP2B1或人OATP2B1对口服阿托伐他汀药代动力学的贡献,发现浓度-时间曲线和药代动力学参数均无差异。然而,在SLCO2B1人源化大鼠和基因敲除动物静脉给药后比较阿托伐他汀的药代动力学时,观察到显著差异。特别是,在人源化动物中,全身暴露(AUC)减少了约40%,而表达人OATP2B1的动物的清除率(CL)高57%。这些结果表明,人OATP2B1影响阿托伐他汀静脉给药后的药代动力学,最有可能是通过促进肝脏摄取。重要性语句Wildtype,rSlco2b1敲除和SLCO2B1人源化Wistar大鼠的特征在于大鼠和人SLCO2B1/OATP2B1的表达。阿托伐他汀在24小时内的药代动力学研究在男性野生型,rSlco2b1-敲除,和SLCO2B1人源化大鼠。单剂量静脉注射后,与基因敲除动物相比,在SLCO2B1人源化大鼠中观察到较低的全身暴露量和清除率增加,表明OATP2B1对肝脏清除率有贡献.
The organic anion transporting polypeptide (OATP) 2B1 is considered an emerging drug transporter that is found expressed in pharmacokinetically relevant organs such as the liver, small intestine, and kidney. Despite its interaction with various substrate drugs, the understanding of its in vivo relevance is still limited. In this study, we first validated the interaction of atorvastatin with rat OATP2B1 using transiently transfected HeLa cells. Moreover, we characterized our rSlco2b1-knockout and SLCO2B1-knockin rats for mRNA, protein expression, and localization of OATP2B1 in the liver, small intestine, and kidney. The transporter showed the highest expression in the liver followed by the small intestine. In humanized rats, human OATP2B1 is localized on the sinusoidal membrane of hepatocytes. In enterocytes of wild-type and humanized rats, the transporter was detected in the luminal membrane with the vast majority being localized subapical. Subsequently, we assessed atorvastatin pharmacokinetics in male wild-type, rSlco2b1-knockout, and SLCO2B1-knockin rats after a single-dose administration (orally and intravenously). Investigating the contribution of rat OATP2B1 or human OATP2B1 to oral atorvastatin pharmacokinetics revealed no differences in concentration-time profiles or pharmacokinetic parameters. However, when comparing the pharmacokinetics of atorvastatin after intravenous administration in SLCO2B1-humanized rats and knockout animals, notable differences were observed. In particular, the systemic exposure (area under the curve) decreased by approximately 40% in humanized animals, whereas the clearance was 57% higher in animals expressing human OATP2B1. These findings indicate that human OATP2B1 influences pharmacokinetics of atorvastatin after intravenous administration, most likely by contributing to the hepatic uptake. SIGNIFICANCE STATEMENT: Wild-type, rSlco2b1-knockout, and SLCO2B1-humanized Wistar rats were characterized for the expression of rat and human SLCO2B1/OATP2B1. Pharmacokinetic studies of atorvastatin over 24 hours were conducted in male wild-type, rSlco2b1-knockout, and SLCO2B1-humanized rats. After a single-dose intravenous administration, a lower systemic exposure and an increase in clearance were observed in SLCO2B1-humanized rats compared with knockout animals indicating a contribution of OATP2B1 to the hepatic clearance.