title: Enantioselective N-demethylation and hydroxylation of sibutramine in human liver microsomes and recombinant cytochrome p-450 isoforms.
abstract: The enantioselective metabolism of sibutramine was examined using human liver microsomes (HLM) and recombinant cytochrome P-450 (CYP) isoforms. This drug is metabolized to N-mono-desmethyl- (M1) and N,N-di-desmethylsibutramine (M2), and subsequent hydroxylation results in hydroxyl M1 (HM1) and hydroxyl M2 (HM2). No significant difference was noted in formation of M1from sibutramine between R- and S-sibutramine in HLM. However, S-enantiomers of M1 and M2 were preferentially metabolized to M2, HM1, and HM2compared to R-enantiomers in HLM, and intrinsic clearance (Clint) ratios of S-enantiomers/R-enantiomers were 1.97, 4.83, and 9.94 for M2, HM1, and HM2, respectively. CYP3A4 and CYP3A5 were only involved in the formation of M1, whereas CYP2B6 and CYP2C19 were responsible for all metabolic reactions of sibutramine. CYP2C19 and CYP3A5 displayed catalytic preference for S-sibutramine to S-M1, whereas CYP2B6 and CYP3A4 showed little or no stereoselectivity in metabolism of sibutramine to M1. In the case of M2 formation, CYP2B6 metabolized S-M1 more rapidly than R-M1 with a Clint ratio of 2.14. However, CYP2C19 catalyzed less S-M1 than R-M1 and the Clint ratio of S-M1 to R-M1 was 0.65. The most significant enantioselectivity was observed in formation of HM1 from M1, and HM2 from M2. CYP2B6 and CYP2C19 exhibited preferential catalysis of formation of hydroxyl metabolites from S-enantiomers rather than R-enantiomers. These results indicate that S-sibutramine was more rapidly metabolized by CYP isoforms than R-sibutramine, and that enantioselective metabolism needs to be considered in drug interactions involving sibutramine and co-administered drugs.
authors.affiliation: a Albany Molecular Research, Inc. (AMRI) , Waluj , Aurangabad , India.
authors.forename: Dhananjay D
authors.initials: DD
authors.lastname: Shinde
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Jeong
authors.forename: Yang-Weon
authors.initials: YW
authors.lastname: Kim
authors.forename: Ji-Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D002853:Chromatography, Liquid; D003503:Cyclobutanes / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism*; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry
chemical_list: D003503:Cyclobutanes; D007527:Isoenzymes; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; C058254:sibutramine