Chemical, enzymatic, and human enantioselective S-oxygenation of cimetidine.
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).
Cashman
J R
JR
Department of Pharmaceutical Chemistry, University of California, San Francisco.
Park
S B
SB
Yang
Z C
ZC
Washington
C B
CB
Gomez
D Y
DY
Giacomini
K M
KM
Brett
C M
CM
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
D002927:Cimetidine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D010100:Oxygen