Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Clin Pharmacol Ther. 2012 Nov;92(5):642-50. doi: 10.1038/clpt.2012.106. Epub 2012 Sep 19.
Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-Rex293 cells, erythromycin was found to be a substrate for OATP1B11A (wild type) with a Michaelis-Menten constant of ~13 µmol/l, and that its transport was reduced by ~50% in cells expressing OATP1B15 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B1*5, was associated with a decline in erythromycin metabolism (P = 0.0072). These results suggest that impairment of OATP1B1 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
先前的研究表明，红霉素作为 CYP3A4 活性的探针，其药代动力学特征受到肝溶质载体的抑制剂或诱导剂的影响。我们假设这些相互作用是由 OATP1B1（基因符号 SLCO1B1）介导的，OATP1B1 是一种在肝细胞基底外侧表面表达的多肽。使用稳定转染的 Flp-In T-Rex293 细胞，发现红霉素是 OATP1B11A（野生型）的底物，米氏常数约为 13µmol/l，而在表达 OATP1B15（V174A）的细胞中，其转运减少了约 50%。在缺乏小鼠同源转运蛋白 Oatp1b2 的情况下，红霉素的代谢率下降了 52%（P=0.000043）。与这些观察结果一致，在人类中，编码 OATP1B1*5 的 SLCO1B1（c.521T>C 变异，rs4149056）与红霉素代谢下降相关（P=0.0072）。这些结果表明，OATP1B1 功能的损害可改变红霉素的代谢，而与 CYP3A4 活性的变化无关。
