TY - JOUR T1 - Chemical, enzymatic, and human enantioselective S-oxygenation of cimetidine. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 587 LP - 597 VL - 21 IS - 4 AU - J R Cashman AU - S B Park AU - Z C Yang AU - C B Washington AU - D Y Gomez AU - K M Giacomini AU - C M Brett Y1 - 1993/07/01 UR - http://dmd.aspetjournals.org/content/21/4/587.abstract N2 - 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). ER -