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Effect of Terbinafine on the Pharmacokinetics and Pharmacodynamics of Desipramine in Healthy Volunteers Identified as Cytochrome P450 2D6 (CYP2D6) Extensive Metabolizers
Author(s) -
Madani Soraya,
Barilla Denise,
Cramer Jeffrey,
Wang Yibin,
Paul Carle
Publication year - 2002
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/009127002762491299
Subject(s) - desipramine , cyp2d6 , terbinafine , pharmacology , pharmacokinetics , pharmacodynamics , metabolite , active metabolite , discontinuation , medicine , oral administration , cytochrome p450 , antidepressant , metabolism , itraconazole , dermatology , antifungal , hippocampus
Terbinafine‐CYP2D6 inhibition was evaluated by assessing 48‐hour concentration‐time profiles of the tricyclic antidepressant desipramine in 12 healthy volunteers identified as extensive cytochrome P450 2D6 (CYP2D6) metabolizers by genotyping and phenotyping. Pharmacokinetics was evaluated at baseline (50 mg oral desipramine given alone), steady state (after 250 mg oral terbinafine for 21 days), and 2 and 4 weeks after terbinafine discontinuation. Pharmacodynamics was evaluated before and 2 hours after each desipramine administration, using Mini‐Mental Status Examination (MMSE) and ECG. Terbinafine administration inhibited CYP2D6 metabolism, as indicated by the significant increase in desipramine C max (19 ng/ml vs. 36 ng/ml) and AUC 0‐∞ (482 ng•h/ml vs. 2383 ng•h/ml) and decrease in AUC 0–24 and C max of the CYP2D6‐mediated metabolite, 2‐hydroxydesipramine. In addition, the C max and AUC 0‐∞ of desipramine and metabolite were still elevated 4 weeks after terbinafine discontinuation. Caution should be exercised when coprescribing terbinafine and drugs metabolized by CYP2D6, particularly those with a narrow therapeutic index.