Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
J Pharm Sci. 2013 Sep;102(9):3427-35. doi: 10.1002/jps.23477. Epub 2013 Feb 25.
Previously, we reported a long-lasting inhibition of transport mediated by organic anion-transporting polypeptides (OATPs) in humans and rats by cyclosporin A (CsA). In the present study, we examined the effects of several other compounds on OATP1B1-mediated transport, with a focus on long-lasting inhibition. Effects of coincubation, preincubation, or preincubation plus coincubation of 12 compounds on uptake of estrone 3-sulfate (E1 S) in OATP1B1-expressing HEK293T cells were examined. The OATP1B1 inhibitors used in the present study inhibited OATP1B1-mediated uptake of E1 S in a concentration-dependent manner. Among them, saquinavir and ritonavir in addition to CsA exhibited long-lasting inhibitory effects on OATP1B1-mediated transport of E1 S at ≥ 5 and 25 μM, respectively, even after they were washed out from the incubation buffer. After preincubation with saquinavir, its inhibitory effect on OATP1B1 remained for at least 6 h, whereas the effect of ritonavir did not remain. Protein expression of OATP1B1 was not altered by preincubation with 25 μM saquinavir or ritonavir. The present study firstly showed that saquinavir and ritonavir as well as CsA have long-lasting inhibitory effects on OATP1B1. But, at plasma unbound concentrations of saquinavir and ritonavir in clinical situations, they may not cause long-lasting inhibition of OATP1B1.
先前，我们报道了环孢素 A（CsA）在人和大鼠中对有机阴离子转运多肽（OATPs）介导的转运具有持久抑制作用。在本研究中，我们研究了其他几种化合物对 OATP1B1 介导的转运的影响，重点关注持久抑制作用。考察了 12 种化合物的共孵育、预孵育或预孵育加共孵育对 OATP1B1 表达的 HEK293T 细胞摄取雌酮 3-硫酸盐（E1 S）的影响。本研究中使用的 OATP1B1 抑制剂以浓度依赖的方式抑制 E1 S 的 OATP1B1 介导摄取。其中，saquinavir 和 ritonavir 除 CsA 外，分别在≥5 和 25 μM 时对 E1 S 的 OATP1B1 介导转运表现出持久抑制作用，即使在从孵育缓冲液中洗脱后也是如此。用 saquinavir 预孵育后，其对 OATP1B1 的抑制作用至少持续 6 小时，而 ritonavir 的作用则不持续。用 25 μM saquinavir 或 ritonavir 预孵育不会改变 OATP1B1 的蛋白表达。本研究首次表明 saquinavir、ritonavir 和 CsA 对 OATP1B1 具有持久抑制作用。但是，在临床情况下 saquinavir 和 ritonavir 的血浆未结合浓度下，它们可能不会对 OATP1B1 产生持久抑制作用。
