Shen Hong, Dai Jun, Liu Tongtong, Cheng Yaofeng, Chen Weiqi, Freeden Chris, Zhang Yingru, Humphreys W Griffith, Marathe Punit, Lai Yurong
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
J Pharmacol Exp Ther. 2016 May;357(2):382-93. doi: 10.1124/jpet.116.232066. Epub 2016 Feb 23.
Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6- and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7- and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6- to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b(-/-)), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1- to 18.4-fold; P < 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.
抑制有机阴离子转运多肽（OATP）1B功能可导致严重的临床药物相互作用，因此在药物研发过程中必须对这类相互作用的可能性进行全面评估。因此，目前需要可与临床研究结合使用的、灵敏且特异的OATP功能生物标志物。在本研究中，进行了临床前评估，以确定粪卟啉（CPs）I和III作为肝脏OATP功能活性标志物的适用性。在单独表达人OATP1B1（hOATP1B1）、hOATP1B3、食蟹猴OATP1B1（cOATP1B1）或cOATP1B3的人胚肾（HEK）293细胞以及人和猴肝细胞中观察到CPs I和III的主动摄取。环孢素A（100 mg/kg，口服）使CPs I和III的血浆浓度曲线下面积（AUC）显著增加2.6倍和5.2倍，而利福平（15 mg/kg，口服）分别使AUC增加2.7倍和3.6倍。随着全身暴露增加，两种异构体在猴尿中的排泄量从1.6倍增加到4.3倍。与这一发现一致，当联合给予OATP1B抑制剂时，食蟹猴中瑞舒伐他汀（RSV）的AUC增加。在Oatp1a/1b基因簇敲除小鼠（Oatp1a/1b(-/-)）中，血浆和尿液中的CPs与野生型动物相比显著增加（7.1倍至18.4倍；P < 0.001），这也与血浆RSV暴露的变化一致（增加14.6倍）。我们得出结论，血浆和尿液中的CPs I和III是反映肝脏OATP功能的新型内源性生物标志物，这些测量结果有可能纳入早期临床评估的设计中。
