AstraZeneca Pharmaceuticals, Molecular Toxicology, Safety Assessment UK, Mereside, Alderley Park Macclesfield, Cheshire SK10 4TG, UK.
Drug Metab Dispos. 2012 Jan;40(1):130-8. doi: 10.1124/dmd.111.040758. Epub 2011 Sep 30.
Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.
抑制人胆汁盐输出泵（BSEP：ABCB11）的活性被认为在药物性肝损伤（DILI）中起作用。为了增强对 BSEP 抑制与 DILI 之间关系的理解，在体外研究了 85 种药物对人 BSEP（hBSEP）及其大鼠同源物（rBsep）的抑制作用。这是通过定量测定在 Sf21 昆虫细胞表达的蛋白的倒置质膜小泡中 ATP 依赖性[3H]牛磺胆酸钠摄取来探索的。在这些药物中，有 40 种表现出体外转运体抑制的证据，并且 hBSEP 和 rBsep 活性抑制效力值之间观察到密切相关性（r²=0.94），尽管有 12 种药物对 hBSEP 的抑制作用比 rBsep 强 2 倍以上。在引起胆汁淤积/混合性 DILI 的药物中，hBSEP 抑制的中位效力高于引起肝细胞性或无 DILI 的药物，而 hBSEP 抑制的 IC50 <300 μM 的发生率也是如此。所有 hBSEP IC50 <300 μM 的药物分子量均大于 250，ClogP >1.5，非极性表面积大于 180Å。hBSEP 的 IC50 或未结合血浆浓度（C（max，u））与药物是否引起 DILI 之间没有明显区别。然而，所有 17 种 hBSEP IC50 <100 μM 和 C（max，u）>0.002 μM 的药物均引起 DILI。总体而言，这些数据表明，hBSEP/rBsep 的抑制与许多药物在人类中引起胆汁淤积性 DILI 的倾向相关，并且与它们的一些物理化学性质相关。
