Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test

Background: The ultrarapid metabolizer phenotype of the cytochrome P4502D6 (CYP2D6) enzyme has been considered a relevant cause of nonresponse to anti depressant drug therapy. Prescribing high doses of antidepressants to such patients leads to high concentrations of potentially toxic metabolites and an increased risk for adverse reactions. Normalization of the metabolic sta tus of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with an tidepressants. Methods: Five ultrarapid metabolizers with a CYP2D6 gene duplication or tri plication were treated with 25 mg nortriptyline twice a day for 3 consecuti ve weeks, alone during the first week and concomitantly with the CYP2D6 inh ibitor paroxetine 10 mg or 20 mg twice a day, respectively, during the seco nd and third weeks. After the third week, nortriptyline was discontinued an d the subjects were treated with paroxetine 20 mg twice a day during the fo urth study week. At the end of each study week, the steady-state pharmacoki netic parameters of nortriptyline or paroxetine were determined within the dose interval. In addition, the CYP2D6 phenotype was determined by debrisoq uin (INN, debrisoquine) test at baseline and at the end of each study phase . Treatment-related adverse events were recorded during drug administration and for 1 week thereafter. Results. All 5 subjects had very low (subtherapeutic) nortriptyline concent rations after 7 days' treatment with nortriptyline only. Addition of paroxe tine 10 mg twice a day to the nortriptyline regimen resulted in a change in all individuals to the "normal" extensive debrisoquine metabolizer phenoty pe, and therapeutic plasma nortriptyline concentrations were achieved in 4 of 5 subjects after a 3 times mean increase in nortriptyline trough concent ration (P = .0011). Doubling the paroxetine dose caused a 15 times mean inc rease in paroxetine trough concentration (P < .001), indicating strong inhi bition by paroxetine of its own metabolism. The high paroxetine concentrati ons in 2 subjects caused them to have the poor debrisoquine metabolizer phe notype and resulted in a further increase in plasma nortriptyline trough co ncentration (P = .0099). A strong correlation (rank correlation coefficient [r(s)] = 0.89; P < .0001) was observed between paroxetine and nortriptylin e trough concentrations. Paroxetine also significantly decreased the fluctu ation of nortriptyline concentrations within the dose interval. One subject discontinued the study after the second study week because of adverse effe cts; otherwise, the study drugs were well tolerated. Conclusions: Paroxetine, with a daily dosage from 20 to 40 mg, is an effect ive tool in normalizing the metabolic status of CYP2D6 ultrarapid metaboliz ers.