10-hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CΥP2D6 genes

Objective: To investigate the disposition and effects of nortriptyline and its major metabolite 10-hydroxynortriptyline in panels of white subjects with different CYP2D6 genotypes, including those with duplicated and multiduplicated CYP2D6*2 genes and to evaluate the contribution of the number of functional CYP2D6 alleles to the metabolism of nortriptyline, used here as a model drug for CYP2D6 substrates. Methods: Oral single doses of 25 to 50 mg nortriptyline were given to five poor metabolizers of debrisoquin (INN, debrisoquine) with no functional CYP2D6 gene, five extensive metabolizers with one functional CYP2D6 gene, five extensive metabolizers with two functional CYP2D6 genes, five ultrarapid metabolizers with duplicated CYP2D6*2 genes, and one ultrarapid metabolizer with 13 copies of the CYP2D6*2 gene. Plasma kinetics of nortriptyline and 10-hydroxynortriptyline were analyzed. Anticholinergic effects (inhibition of salivation and accommodation disturbances), sedation, blood pressure, and effect on supine and erect pulse rate were measured. Results: There was a dear relation between the CYP2D6 genotype and the plasma kinetics of nortriptyline and 10-hydroxynortriptyline. The proportion between the apparent oral clearances of nortriptyline in the groups with 0, 1, 2, 3, and 13 functional genes was 1:1:4:5:17. The proportions between AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratios in the groups with 0, 1, 2, 3, and 13 functional genes were 36:25:10:4:1. Oral plasma clearance of nortriptyline and AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratio bath correlated significantly with the debrisoquin metabolic ratio (r(s) = -0.89, p = 0.0001; r(s) = 0.92, P = 0.0001). Although ultrarapid metabolizer subjects were given double the nortriptyline dose (50 mg), inhibition of salivation was not more pronounced compared with the other genotype groups given 25 mg nortriptyline. Conclusion: The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 gents for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.