Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes.
The 2-hydroxylation of desmethylimipramine (DMI) and the 4-hydroxylation of debrisoquine (D) were studied in healthy subjects and in human liver microsomes. A single oral dose of DMI (25 mg) was given to 18 healthy subjects previously phenotyped with D (13 rapid and five slow hydroxylators). Urine was collected for 24 hr and DMI and total 2-hydroxydesmethylimipramine (2-OH-DMI) levels were determined by HPLC. The urinary ratio DMI/2-OH-DMI correlated strongly (r = 0.92) with the urinary ratio of D to 4-hydroxydebrisoquine (D/4-OH-D). The two hydroxylations were also studied in human liver microsomes from 10 different subjects. Formation rates of the hydroxylated metabolites correlated strongly (r = 0.869). Moreover, D competitively inhibited the 2-hydroxylation of DMI. These findings suggest that both are hydroxylated by the same cytochrome P-450 isozyme.
D000328:Adult; D002851:Chromatography, High Pressure Liquid; D003647:Debrisoquin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D003891:Desipramine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007546:Isoquinolines / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype
D007546:Isoquinolines; C012359:4-hydroxydebrisoquin; D003891:Desipramine; C028653:2-hydroxydesipramine; D003647:Debrisoquin