Effect of terbinafine on the pharmacokinetics and pharmacodynamics of desipramine in healthy volunteers identified as cytochrome P450 2D6 (CYP2D6) extensive metabolizers.
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 EGG. Terbinafine administration inhibited CYP2D6 metabolism, as indicated by the significant increase in desipramine C(max) (19 ng/ml vs. 36 ng/ml) and AUC0-infinity (482 ng.h/ml vs. 2383 ng.h/ml) and decrease in AUC0-24 and C(max) of the CYP2D6-mediated metabolite, 2-hydroxydesipramine. In addition, the C(max) and AGUC0-infinity 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.
Madani
Soraya
S
Clinical Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936-1080, USA.
Barilla
Denise
D
Cramer
Jeffrey
J
Wang
Yibin
Y
Paul
Carle
C
D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003891:Desipramine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D003915:Dextromethorphan / Q000652:urine; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000009:adverse effects / Q000494:pharmacology*; D010641:Phenotype; D011237:Predictive Value of Tests; D000077291:Terbinafine; D013997:Time Factors
D000890:Anti-Infective Agents; D000929:Antidepressive Agents, Tricyclic; D009281:Naphthalenes; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D000077291:Terbinafine; D003891:Desipramine