Stereo- and regioselectivity of hepatic oxidation in man--effect of the debrisoquine/sparteine phenotype on bufuralol hydroxylation.
The influence of the debrisoquine/sparteine-type of oxidation polymorphism on plasma bufuralol concentration and the pattern of urine metabolites was studied in extensive and poor metabolizer subjects. (+)- and (-)-bufuralol, and (+)- and (-)-OH-bufuralol in plasma were determined by enantioselective HPLC, and urinary bufuralol and its metabolites were assayed by gas chromatography-mass spectrometry. Three hours after administration of racemic bufuralol the plasma (-)/(+) isomeric ratio for unchanged bufuralol was 1.84 in extensive metabolizers, indicating preferential clearance of the (+)-isomer through aliphatic 1'-hydroxylation and glucuroconjugation, while the (-)-isomer was mainly eliminated by aromatic 4-hydroxylation. Poor metabolizers were characterized by impaired 1'- and 4-hydroxylation, with almost total abolition of the stereoselectivity of these reactions. The data strongly suggest that both 1'- and 4-hydroxylation are catalyzed by the same enzyme. These in vivo observations are in agreement with recent in vitro data obtained in human liver microsomes from phenotyped patients and support the concept of deficiency of a highly stereoselective cytochrome P-450 isozyme as the cause of this polymorphism.
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D003647:Debrisoquin / Q000378:metabolism*; D004983:Ethanolamines / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006900:Hydroxylation; D007546:Isoquinolines / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D011110:Polymorphism, Genetic; D013034:Sparteine / Q000378:metabolism; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D007546:Isoquinolines; D013034:Sparteine; C010831:bufuralol; D003647:Debrisoquin