title: Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7.
abstract: UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 μM and 31.1 μM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 μM and 3.1 μM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism.
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, P.R. China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.forename: Haina
authors.initials: H
authors.lastname: Wang
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.forename: Dong-Xue
authors.initials: DX
authors.lastname: Sun
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Wang
authors.forename: Mo
authors.initials: M
authors.lastname: Hong
authors.forename: Ting
authors.initials: T
authors.lastname: Huang
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Zeng
mesh_terms: D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D013237:Stereoisomerism
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C007005:carprofen
keywords: UDP-glucuronosyltransferase (UGT); carprofen; enantioselective inhibition