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 antidepressant 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 status of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with antidepressants.


METHODS
Five ultrarapid metabolizers with a CYP2D6 gene duplication or triplication were treated with 25 mg nortriptyline twice a day for 3 consecutive weeks, alone during the first week and concomitantly with the CYP2D6 inhibitor paroxetine 10 mg or 20 mg twice a day, respectively, during the second and third weeks. After the third week, nortriptyline was discontinued and the subjects were treated with paroxetine 20 mg twice a day during the fourth study week. At the end of each study week, the steady-state pharmacokinetic parameters of nortriptyline or paroxetine were determined within the dose interval. In addition, the CYP2D6 phenotype was determined by debrisoquin (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 concentrations after 7 days' treatment with nortriptyline only. Addition of paroxetine 10 mg twice a day to the nortriptyline regimen resulted in a change in all individuals to the "normal" extensive debrisoquine metabolizer phenotype, and therapeutic plasma nortriptyline concentrations were achieved in 4 of 5 subjects after a 3 times mean increase in nortriptyline trough concentration (P =.0011). Doubling the paroxetine dose caused a 15 times mean increase in paroxetine trough concentration (P <.001), indicating strong inhibition by paroxetine of its own metabolism. The high paroxetine concentrations in 2 subjects caused them to have the poor debrisoquine metabolizer phenotype and resulted in a further increase in plasma nortriptyline trough concentration (P =.0099). A strong correlation (rank correlation coefficient [r(s)] = 0.89; P <.0001) was observed between paroxetine and nortriptyline trough concentrations. Paroxetine also significantly decreased the fluctuation of nortriptyline concentrations within the dose interval. One subject discontinued the study after the second study week because of adverse effects; otherwise, the study drugs were well tolerated.


CONCLUSIONS
Paroxetine, with a daily dosage from 20 to 40 mg, is an effective tool in normalizing the metabolic status of CYP2D6 ultrarapid metabolizers.
Laine
K
K
Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden. karlai@utu.fi
Tybring
G
G
Härtter
S
S
Andersson
K
K
Svensson
J O
JO
Widén
J
J
Bertilsson
L
L
D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003647:Debrisoquin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007024:Hypotension, Orthostatic / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000235:genetics; D009661:Nortriptyline / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D017374:Paroxetine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010641:Phenotype; D014202:Tremor / Q000139:chemically induced; D014987:Xerostomia / Q000139:chemically induced
D000929:Antidepressive Agents, Tricyclic; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C013567:10-hydroxynortriptyline; D017374:Paroxetine; C012359:4-hydroxydebrisoquin; D009661:Nortriptyline; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin