Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Blindern, Oslo, Norway.
Drug Metab Dispos. 2010 Sep;38(9):1499-504. doi: 10.1124/dmd.110.032268. Epub 2010 Jun 2.
The aim of this study was to investigate the potential of calcineurin inhibitors [cyclosporine A (CsA) and tacrolimus (Tac)] to inhibit cellular uptake of atorvastatin mediated by the liver-specific organic anion-transporting polypeptide 1B1 (OATP1B1) in vitro. Patients with solid organ transplants are frequently treated with HMG-CoA reductase inhibitors (statins). CsA increases atorvastatin systemic exposure severalfold, an effect not observed with Tac. The effect of CsA and Tac on atorvastatin transport via OATP1B1 was investigated in transfected human embryonic kidney 293 cells. An in vitro-in vivo extrapolation (IVIVE) was performed to estimate the clinical potential for CsA and Tac to inhibit OATP1B1-mediated transport. CsA inhibited OATP1B1-mediated uptake of atorvastatin approximately 90-fold more efficiently than Tac, with half-maximal inhibitory concentration (IC(50)) values of 0.021 +/- 0.004 and 1.99 +/- 0.42 muM, respectively. Coincubation compared with preincubation with CsA showed a 20-fold lower inhibitory capacity, with an IC(50) value of 0.47 +/- 0.34 muM. The IVIVE showed that clinically obtainable concentrations of CsA, but not Tac, inhibit OATP1B1 transport of atorvastatin. CsA inhibition ranged from 28 to 77% within a dosing interval, whereas it was less than 1% for Tac, considering free concentrations and assuming competitive inhibition. This does not fully explain the clinically observed interaction with CsA, suggesting that a more complex inhibitory mechanism may be present. This is also supported by the decreased IC(50) value of CsA after preincubation. This study provides evidence that OATP1B1 inhibition is a relevant mechanism for the interaction observed between CsA and atorvastatin.
本研究旨在探讨钙调神经磷酸酶抑制剂（环孢素 A [CsA] 和他克莫司 [Tac]）是否具有抑制肝特异性有机阴离子转运多肽 1B1（OATP1B1）介导的阿托伐他汀细胞摄取的潜力。接受实体器官移植的患者经常接受 HMG-CoA 还原酶抑制剂（他汀类药物）治疗。CsA 使阿托伐他汀的全身暴露量增加数倍，而 Tac 则无此作用。在转染的人胚肾 293 细胞中研究了 CsA 和 Tac 对 OATP1B1 介导的阿托伐他汀转运的影响。进行了体外-体内外推法（IVIVE）以评估 CsA 和 Tac 抑制 OATP1B1 介导的转运的临床潜力。与 Tac 相比，CsA 对 OATP1B1 介导的阿托伐他汀摄取的抑制作用效率高 90 倍，半抑制浓度（IC50）值分别为 0.021 +/- 0.004 和 1.99 +/- 0.42 microM。与 CsA 预孵育相比，共孵育显示出 20 倍的低抑制能力，IC50 值为 0.47 +/- 0.34 microM。IVIVE 表明，临床上可获得的 CsA 浓度但不是 Tac 浓度可抑制 OATP1B1 转运阿托伐他汀。考虑到游离浓度并假设竞争性抑制，CsA 的抑制范围在剂量间隔内为 28%至 77%，而 Tac 则小于 1%。这不能完全解释与 CsA 观察到的相互作用，表明可能存在更复杂的抑制机制。这也得到了 CsA 预孵育后 IC50 值降低的支持。本研究提供了证据表明 OATP1B1 抑制是 CsA 与阿托伐他汀观察到的相互作用的相关机制。
