POLYMORPHIC 2-HYDROXYLATION OF DESIPRAMINE - A POPULATION AND FAMILY STUDY

We have studied desipramine hydroxylation capacity, determined as the metabolic ratio of desipramine to 2-hydroxydesipramine in the urine af ter a single oral dose of 10 mg of desipramine, in 340 Swedish Caucasi ans, including the members of 45 two-generation families. Desipramine metabolic ratios were bimodally distributed among 237 unrelated subjec ts and 8 % were poor metabolizers. There was a strong correlation betw een the metabolic ratios for desipramine and debrisoquine in 337 subje cts phenotyped with both drugs and there was no dissociation between t heir capacities to hydroxylate desipramine and debrisoquine. Complex s egregation analysis in the 45 families gave evidence for a major locus with incomplete recessivity (d = 0.14) controlling the 2-hydroxylatio n of desipramine. Similar results were obtained in segregation analysi s for debrisoquine. There was evidence for linkage between the CYP2D6 gene and the gene regulating the hydroxylation of desipramine and debr isoquine. This study has provided unequivocal evidence that the capaci ty to 2-hydroxylate desipramine is polymorphic and under similar genet ic control to the hydroxylation of debrisoquine.