Campbell Scott D, de Morais Sonia M, Xu Jinghai J
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton Laboratory, Eastern Point Road, MS 8118W-131, Groton, CT 06340, USA.
Chem Biol Interact. 2004 Nov 20;150(2):179-87. doi: 10.1016/j.cbi.2004.08.008.
OATP1B1 (a.k.a. OATP-C, OATP2, LST-1, or SLC21A6) is a liver-specific organic anion uptake transporter and has been shown to be a higher affinity bilirubin uptake transporter than OATP1B3. Using human embryonic kidney (HEK 293) cells stably transfected with OATP1B1, we have studied the effects of indinavir, saquinavir, cyclosporin A, and rifamycin SV on human OATP1B1 transport function. These drugs are potent inhibitors of OATP1B1 transport activity in vitro. We further provide evidence that the calculated fraction of OATP1B1 inhibited at the clinical exposure level correlated very well with the observed hyperbilirubinemia outcome for these drugs in humans. Our data support the hypothesis that inhibition of OATP1B1 is an important mechanism for drug-induced unconjugated hyperbilirubinemia. Inhibition of OATPs may be an important mechanism in drug-drug and drug-endogenous substance interactions.
有机阴离子转运多肽1B1（又称OATP-C、OATP2、LST-1或溶质载体家族21成员6）是一种肝脏特异性有机阴离子摄取转运体，并且已被证明是一种比有机阴离子转运多肽1B3具有更高亲和力的胆红素摄取转运体。利用稳定转染了有机阴离子转运多肽1B1的人胚肾（HEK 293）细胞，我们研究了茚地那韦、沙奎那韦、环孢素A和利福霉素SV对人有机阴离子转运多肽1B1转运功能的影响。这些药物在体外是有机阴离子转运多肽1B1转运活性的强效抑制剂。我们进一步提供证据表明，在临床暴露水平下计算得出的有机阴离子转运多肽1B1被抑制的分数与这些药物在人体中观察到的高胆红素血症结果密切相关。我们的数据支持这样的假说，即有机阴离子转运多肽1B1的抑制是药物性非结合性高胆红素血症的重要机制。有机阴离子转运多肽的抑制可能是药物-药物和药物-内源性物质相互作用中的一个重要机制。
