Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes

Abstract

The 2-hydroxylation of desmethylimipramine (DMI) [a tricyclic antidepressant] 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 5 slow hydroxylators). Urine was collected for 24 h and DMI and total 2-hydroxydesmethylimipramine (2-OH-DMI) levels were determined by HPLC [high performance liquid chromatography]. 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 2 hydroxylations were also studied in human liver microsomes from 10 different subjects. Formation rates of the hydroxylated metabolites correlated strongly (r = 0.869). D competitively inhibited the 2-hydroxylation of DMI. These findings suggest that both are hydroxylated by the same cytochrome P-450 isozyme.