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Inhibition of CYP2D6 with low dose (5 mg) paroxetine in patients with high 10‐hydroxynortriptyline serum levels‐A prospective pharmacokinetic study
Author(s) -
Jessurun Naomi T.,
Vermeulen Windsant Annemieke,
Mikes Oe,
Puijenbroek Eugène P.,
Marum Rob J.,
Grootens Koen,
Derijks Hieronymus J.
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14455
Subject(s) - nortriptyline , cyp2d6 , paroxetine , pharmacokinetics , pharmacology , metabolite , active metabolite , drug interaction , medicine , antidepressant , cytochrome p450 , amitriptyline , metabolism , hippocampus
The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10‐hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50–150 μg/L) and safe hydroxynortriptyline (<200 μg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges.