Pharmacogenetics of desipramine metabolism

There is wide interindividual variation in steady-state plasma concentration of desipramine and other tricyclic antidepressants primarily due to differences in rates of hydroxylation. Several studies have shown that the rate of hydroxylation of desipramine is correlated with the rate of hydroxylation of the genetic probe drug, debrisoquine, which is controlled by monogenic inheritance. However, no population studies of the polymorphic metabolism of antidepressants have been reported. In this study, 59 patients with endogenous depression received a fixed dose of desipramine and the steady-state plasma concentration of desipramine and 2-hydroxydesipramine were determined by high-pressure chromatography. A new statistical approach based on optimizing the fit to a specific stochastic model was utilized to separate the mixture of the three genotypes: homozygous extensive (AA), heterozygous extensive (Aa) and poor (aa) metabolizers. The proportions of the genotypes are 0.43, 0.45 and 0.12, respectively. The gene frequency of the low-activity allele is 0.34 and that of the high-activity allele is 0.66. The means (SD) of the desipramine/2-hydroxydesipramine metabolic ratios of the three genotypes are 1.71 (0.44), 3.32 (1.68) and 23.32 (10.03). These data suggest that the heterozygous genotype has half the metabolic activity of the homozygous extensive metabolizer and that the poor metabolizer genotype has negligible metabolic activity.