尽管有机阴离子转运多肽(OATP)介导的肝摄取在总体药代动力学水平上在啮齿动物和人类之间通常是保守的,存在三种主要的肝脏OATPs,在底物和抑制剂亲和力上有广泛的重叠,缺乏啮齿动物-人类直向同源物排除了单基因敲除/敲入发现的临床翻译。目前,普伐他汀的药代动力学和组织分布的变化,阿托伐他汀,辛伐他汀,和羧基二氯荧光素在缺乏三种主要肝燕麦亚型的oatp1a/1b基因敲除小鼠中进行了研究,以及在具有人OATP1B1或OATP1B3的肝脏特异性敲入的敲除小鼠中。相对于野生型对照,Oatp1a/1b基因敲除小鼠表现出静脉内增加1.6-至19倍,口服药物暴露增加2.1-至115倍,由于33%-75%的间隙下降,14%-60%的分配量减少,和≤74倍的口服生物利用度增加,变化的幅度取决于oatp1a/1b对药代动力学的贡献。Oatp1a/1b基因敲除小鼠的肝脏药物分布降低了4.2至196倍;肾脏的分布衰减不太明显,大脑,心脏,和骨骼肌。OATP1B1或OATP1B3的爆震部分恢复控制间隙,volume,和生物利用度值(增加24%-142%,≤47%的增长,和≤77%下降与击倒,分别),这样敲入药代动力学谱位于敲除和野生型小鼠之间。与肝脏特异性人源化一致,仅肝脏药物分布部分恢复(1.3至6.5倍增加vs.淘汰赛)。OATP1B1人源化和基因敲除小鼠的暴露和肝脏分布变化预测了OATP1B1对口服暴露的临床影响以及对人类肝脏摄取他汀类药物的贡献在1.7倍以内,但仅在校正人/人源化小鼠肝脏相对蛋白表达因子后(OATP1B1=2.2,OATP1B3=0.30)。
Although organic anion transporting polypeptide (OATP)-mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major hepatic OATPs with broad overlap in substrate and inhibitor affinity, and absence of rodent-human orthologs preclude clinical translation of single-gene knockout/knockin findings. At present, changes in pharmacokinetics and tissue distribution of pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein were studied in oatp1a/1b-knockout mice lacking the three major hepatic oatp isoforms, and in knockout mice with liver-specific knockin of human OATP1B1 or OATP1B3. Relative to wild-type controls, oatp1a/1b-knockout mice exhibited 1.6- to 19-fold increased intravenous and 2.1- to 115-fold increased oral drug exposure, due to 33%-75% decreased clearance, 14%-60% decreased volume of distribution, and ≤74-fold increased oral bioavailability, with the magnitude of change depending on the contribution of oatp1a/1b to pharmacokinetics. Hepatic drug distribution was 4.2- to 196-fold lower in oatp1a/1b-knockout mice; distributional attenuation was less notable in kidney, brain, cardiac, and skeletal muscle. Knockin of OATP1B1 or OATP1B3 partially restored control clearance, volume, and bioavailability values (24%-142% increase, ≤47% increase, and ≤77% decrease vs. knockout, respectively), such that knockin pharmacokinetic profiles were positioned between knockout and wild-type mice. Consistent with liver-specific humanization, only hepatic drug distribution was partially restored (1.3- to 6.5-fold increase vs. knockout). Exposure and liver distribution changes in OATP1B1-humanized versus knockout mice predicted the clinical impact of OATP1B1 on oral exposure and contribution to human hepatic uptake of statins within 1.7-fold, but only after correcting for human/humanized mouse liver relative protein expression factor (OATP1B1 = 2.2, OATP1B3 = 0.30).