title: Comparison of the inhibitory effects of tolcapone and entacapone against human UDP-glucuronosyltransferases.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xia
authors.initials: X
authors.lastname: Lv
authors.affiliation: RSKT Biopharma Inc., Dalian 116023, China.
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Dalian Medical University, Dalian 116044, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.affiliation: RSKT Biopharma Inc., Dalian 116023, China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: 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.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Wu
authors.affiliation: RSKT Biopharma Inc., Dalian 116023, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Liu
authors.affiliation: 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. Electronic address: geguangbo@dicp.ac.cn.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China. Electronic address: ylingdicp@gmail.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001577:Benzophenones / Q000494:pharmacology*; D001663:Bilirubin / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006923:Hymecromone / Q000494:pharmacology; D007313:Insecta; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D009596:Nitrophenols / Q000494:pharmacology*; D000077867:Tolcapone; D014268:Trifluoperazine / Q000494:pharmacology
chemical_list: D000978:Antiparkinson Agents; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D020719:Glucuronides; D009570:Nitriles; D009596:Nitrophenols; D014268:Trifluoperazine; D006923:Hymecromone; C071192:entacapone; D000077867:Tolcapone; D014453:Glucuronosyltransferase; D001663:Bilirubin
keywords: Drug-drug interactions (DDI); Entacapone; Inhibitory effects; Tolcapone; UDP-glucosyltransferases