title: Chemical, enzymatic, and human enantioselective S-oxygenation of cimetidine.
abstract: The S-oxygenation of cimetidine was investigated using achiral chemical and chiral chemical and enzymatic S-oxygenation procedures. The products of the reactions were thoroughly characterized by spectral, chiroptical, chromatographic, and stereochemical correlation methods. S-Oxygenation by the Kagan method or in the presence of pig liver microsomes or pig liver flavin-containing monooxygenase (FMO) (form I) all gave essentially identical enantioselectivity: the average enantiomeric excess was -13.4% and the stereopreference was for formation of (+)-cimetidine S-oxide in a ratio of (+)56.7%:(-)43.3%. The profile of immunoreactivity and the effect of metabolism inhibitors on cimetidine S-oxide formation in the presence of pig liver microsomes were consistent with a role of FMO (form I) in enantioselective (+)-cimetidine S-oxide formation. Administration of cimetidine to seven healthy male volunteers provided pharmacokinetic parameters for cimetidine and cimetidine S-oxide that were typical of those for previously reported studies. The urinary cimetidine S-oxide was isolated and the stereopreference was for formation of (-)-cimetidine S-oxide in a ratio of (+)25.5%:(-)74.5%. In good agreement with the enantiomeric enrichment values observed for the adult human urinary metabolite, the relative configuration of cimetidine S-oxide formed in adult human liver microsomes was (+)-15.8%:(-)-84.2%. Because the enantioselectivity and profile of immunoreactivity and the effect of metabolism inhibitors on cimetidine S-oxygenation in adult human liver microsomes are consistent with a role of FMO (form II) in cimetidine S-oxide formation and because the enantioselectivity of cimetidine S-oxide observed in adult humans is similar, we conclude that in vivo, cimetidine is S-oxygenated principally by FMO (form II).
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco.
authors.forename: J R
authors.initials: JR
authors.lastname: Cashman
authors.forename: S B
authors.initials: SB
authors.lastname: Park
authors.forename: Z C
authors.initials: ZC
authors.lastname: Yang
authors.forename: C B
authors.initials: CB
authors.lastname: Washington
authors.forename: D Y
authors.initials: DY
authors.lastname: Gomez
authors.forename: K M
authors.initials: KM
authors.lastname: Giacomini
authors.forename: C M
authors.initials: CM
authors.lastname: Brett
mesh_terms: D000328:Adult; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism; D013237:Stereoisomerism; D013552:Swine
chemical_list: D002927:Cimetidine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D010100:Oxygen