10-HYDROXYLATION OF NORTRIPTYLINE IN WHITE PERSONS WITH 0-FUNCTIONAL,1-FUNCTIONAL, 2-FUNCTIONAL, 3-FUNCTIONAL, AND 13-FUNCTIONAL C-UPSILON-P2D6 GENES

Objective: To investigate the disposition and effects of nortriptyline and its major metabolite 10-hydroxynortriptyline in panels of white s ubjects with different CYP2D6 genotypes, including those with duplicat ed and multiduplicated CYP2D62 genes and to evaluate the contribution of the number of functional CYP2D6 alleles to the metabolism of nortr iptyline, used here as a model drug for CYP2D6 substrates. Methods: Or al single doses of 25 to 50 mg nortriptyline were given to five poor m etabolizers of debrisoquin (INN, debrisoquine) with no functional CYP2 D6 gene, five extensive metabolizers with one functional CYP2D6 gene, five extensive metabolizers with two functional CYP2D6 genes, five ult rarapid metabolizers with duplicated CYP2D62 genes, and one ultrarapi d metabolizer with 13 copies of the CYP2D62 gene. Plasma kinetics of nortriptyline and 10-hydroxynortriptyline were analyzed. Anticholinerg ic effects (inhibition of salivation and accommodation disturbances), sedation, blood pressure, and effect on supine and erect pulse rate we re measured. Results: There was a dear relation between the CYP2D6 gen otype and the plasma kinetics of nortriptyline and 10-hydroxynortripty line. The proportion between the apparent oral clearances of nortripty line 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-hydroxynort riptyline) ratios in the groups with 0, 1, 2, 3, and 13 functional gen es were 36:25:10:4:1. Oral plasma clearance of nortriptyline and AUC(n ortriptyline) to AUC(10-hydroxynortriptyline) ratio bath correlated si gnificantly with the debrisoquin metabolic ratio (r(s) = -0.89, p = 0. 0001; r(s) = 0.92, P = 0.0001). Although ultrarapid metabolizer subjec ts were given double the nortriptyline dose (50 mg), inhibition of sal ivation was not more pronounced compared with the other genotype group s given 25 mg nortriptyline. Conclusion: The results of this study sho w the quantitative importance of the CYP2D6 genotype, especially the p resence of multiple functional CYP2D6 gents for the pharmacokinetics o f nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects wi th multiple copies of functional genes may be of great value for diffe rentiating ultrarapid metabolizers from patients who do not comply wit h the prescription and for assuring adequate drug choice and dosage fo r these patients.