title: Enantioselective carbonyl reduction of eperisone in human liver microsomes.
abstract: Eperisone, 4-ethyl-2-methyl-3-piperidinopropiophenone, is a centrally acting muscle relaxant widely used to relieve muscle stiffness and back pain. In this study, enantioselectivity for carbonyl reduction of eperisone was investigated in human liver microsomes, and the enzymes involved in the carbonyl reduction were characterised. Carbonyl reduction of eperisone predominantly occurred in microsomal fractions and 11β-hydroxysteroid dehydrogenase type 1(11β-HSD 1) played a major role in this reaction as judged by selective inhibition of the activity by BVT-14225 and KR-66344. The kinetic study with (+)-S- and (-)-R-eperisone showed that the formation of the carbonyl reduced metabolite (M5) from the (-)-R-isomer was more efficient than that from the (-)-S-isomer. As eperisone is a racemic compound with one chiral centre, the carbonyl reduced metabolite of eperisone (M5) may have four possible diastereoisomeric structures. Chiral separation of incubation mixtures of racemic eperisone with human liver microsome revealed that (1S, 2S)-M5 and (1R, 2R)-M5 were generated specifically from (+)-S- and (-)-R-eperisone, respectively. Selective formation of anti-diastereomers was further confirmed by incubation of individual enantiomer with microsomes. Carbonyl reduction of eperisone by microsomal 11β-HSD 1 may significantly contribute to the metabolic disposition of eperisone in human and (-)-R-isomer is preferentially reduced by this enzyme.
authors.affiliation: College of Pharmacy, Hanyang University, Ansan, Gyeonggi, Korea.
authors.forename: Hye Hyun
authors.initials: HH
authors.lastname: Yoo
authors.forename: Nam-Sun
authors.initials: NS
authors.lastname: Kim
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Dongyun
authors.initials: D
authors.lastname: Shin
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002244:Carbon / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009125:Muscle Relaxants, Central / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011335:Proadifen / Q000494:pharmacology; D011427:Propiophenones / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D013237:Stereoisomerism; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C522169:BVT.14225; D009125:Muscle Relaxants, Central; D011427:Propiophenones; D013449:Sulfonamides; D013844:Thiazoles; C030848:eperisone; D002244:Carbon; D011335:Proadifen; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1