Interethnic dissociation between debrisoquine and desipramine hydroxylation

Chinese and Caucasian volunteers who had previously participated in a single dose desipramine pharmacokinetic study underwent debrisoquine hydroxylation phenotyping. After a single 10-mg oral dose of debrisoquine, urinary concentrations of the drug and its major metabolite, 4-hydroxy-debrisoquine (4-OHD), from an 8-hour collection were more variable in the Caucasians. Compared to the Chinese, the Caucasian subjects tended to excrete higher mean fractions of the dose as unchanged debrisoquine (10.9 +/- 8.8% vs. 6.3 +/- 2.6%) and 4-OHD (15.9 +/- 13.0% vs. 9.7 +/- 7.7%), although given the high variability the differences did not reach significance. The "metabolic ratio" of urinary debrisoquine to 4-OHD was less than 3 in all 20 subjects, indicating extensive debrisoquine hydroxylation in every volunteer, including two Chinese individuals known to display slow clearance of desipramine. Contrary to expectation, debrisoquine hydroxylation did not correlate with total or hydroxylation clearance of desipramine in either ethnic group singly or combined. This finding is not consistent with assumptions about the genetic equivalence of the primary metabolic pathways of debrisoquine and desipramine.