Kalliokoski A, Niemi M
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Br J Pharmacol. 2009 Oct;158(3):693-705. doi: 10.1111/j.1476-5381.2009.00430.x. Epub 2009 Sep 25.
Membrane transporters are now recognized as important determinants of the transmembrane passage of drugs. Organic anion transporting polypeptides (OATP) form a family of influx transporters expressed in various tissues important for pharmacokinetics. Of the 11 human OATP transporters, OATP1B1, OATP1B3 and OATP2B1 are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of their substrate drugs. OATP1A2 is expressed on the luminal membrane of small intestinal enterocytes and at the blood-brain barrier, potentially mediating drug transport at these sites. Several clinically used drugs have been identified as substrates of OATP transporters (e.g. many statins are substrates of OATP1B1). Some drugs may inhibit OATP transporters (e.g. cyclosporine) causing pharmacokinetic drug-drug interactions. Moreover, genetic variability in genes encoding OATP transporters can result in marked inter-individual differences in pharmacokinetics. For example, a single nucleotide polymorphism (c.521T > C, p.Val174Ala) in the SLCO1B1 gene encoding OATP1B1 decreases the ability of OATP1B1 to transport active simvastatin acid from portal circulation into the liver, resulting in markedly increased plasma concentrations of simvastatin acid and an enhanced risk of simvastatin-induced myopathy. SLCO1B1 polymorphism also affects the pharmacokinetics of many other, but not all (fluvastatin), statins and that of the antidiabetic drug repaglinide, the antihistamine fexofenadine and the endothelin A receptor antagonist atrasentan. This review compiles the current knowledge about the expression and function of human OATP transporters, their substrate and inhibitor specificities, as well as pharmacogenetics.
膜转运蛋白现已被公认为是药物跨膜转运的重要决定因素。有机阴离子转运多肽（OATP）构成了一类摄取转运蛋白家族，在对药代动力学至关重要的各种组织中表达。在11种人类OATP转运蛋白中，OATP1B1、OATP1B3和OATP2B1在肝细胞的窦状膜上表达，可促进其底物药物的肝脏摄取。OATP1A2在小肠肠上皮细胞的腔膜以及血脑屏障处表达，可能介导这些部位的药物转运。几种临床使用的药物已被确定为OATP转运蛋白的底物（例如，许多他汀类药物是OATP1B1的底物）。一些药物可能抑制OATP转运蛋白（例如环孢素），从而导致药代动力学方面的药物相互作用。此外，编码OATP转运蛋白的基因中的遗传变异性可导致药代动力学方面显著的个体间差异。例如，编码OATP1B1的SLCO1B1基因中的一个单核苷酸多态性（c.521T>C，p.Val174Ala）降低了OATP1B1将活性辛伐他汀酸从门静脉循环转运到肝脏的能力，导致辛伐他汀酸的血浆浓度显著升高以及辛伐他汀诱发肌病的风险增加。SLCO1B1多态性还影响许多其他（但不是所有，如氟伐他汀）他汀类药物以及抗糖尿病药物瑞格列奈、抗组胺药非索非那定和内皮素A受体拮抗剂阿曲生坦的药代动力学。本综述汇编了有关人类OATP转运蛋白的表达和功能、其底物和抑制剂特异性以及药物遗传学的当前知识。
