Lv Xia, Wang Xin-Xin, Hou Jie, Fang Zhong-Ze, Wu Jing-Jing, Cao Yun-Feng, Liu Shu-Wen, Ge Guang-Bo, Yang Ling
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China.
RSKT Biopharma Inc., Dalian 116023, China.
Toxicol Appl Pharmacol. 2016 Jun 15;301:42-9. doi: 10.1016/j.taap.2016.04.009. Epub 2016 Apr 16.
Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants (Ki) of tolcapone and entacapone against bilirubin-O-glucuronidation in human liver microsomes (HLM) are determined as 0.68μM and 30.82μM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin-O-glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1.
托卡朋和恩他卡朋是两种具有相似骨架且药理活性相似的强效儿茶酚-O-甲基转移酶（COMT）抑制剂。然而，恩他卡朋是一种非常安全的药物，广泛用于治疗帕金森病，而托卡朋仅在帕金森病患者中有限使用，由于具有肝毒性，需要仔细监测肝功能。本研究旨在研究和比较恩他卡朋和托卡朋对人尿苷二磷酸葡萄糖醛酸转移酶（UGTs）的抑制作用，并从药物相互作用（DDI）的角度评估潜在风险。结果表明，托卡朋和恩他卡朋均对UGT1A1、UGT1A7、UGT1A9和UGT1A10表现出抑制作用。与恩他卡朋相比，托卡朋对UGT1A1、UGT1A7和UGT1A10表现出更强的抑制作用，而它们对UGT1A9的抑制潜力相当。值得注意的是，托卡朋和恩他卡朋对人肝微粒体（HLM）中胆红素-O-葡萄糖醛酸化的抑制常数（Ki）分别测定为0.68μM和30.82μM，这意味着托卡朋对HLM中UGT1A1介导的胆红素-O-葡萄糖醛酸化的抑制效力远高于恩他卡朋。此外，通过血浆药物浓度-时间曲线下面积（AUC）的比值定量预测了托卡朋或恩他卡朋通过抑制人UGT1A1产生的潜在风险。结果表明，托卡朋可能导致胆红素或主要由UGT1A1代谢的药物的AUC显著增加，而恩他卡朋不太可能通过抑制UGT1A1引起显著的药物相互作用。
