Investigation of terbinafine as a CYP2D6 inhibitor in vivo

Background: Terbinafine is an orally active antifungal used in the treatmen t of dermatophytoses. To date, studies evaluating the effect of terbinafine on the cytochromes P450 have failed to show any significant interactions. This prospective open-label study was designed to confirm our previous find ing that terbinafine may inhibit CYP2D6, Methods: Nine healthy volunteers were enrolled in this study-6 genotypicall y consistent with an extensive metabolizer phenotype and 3 genotypic poor m etabolizers for CYP2D6. The change in CYP2D6 enzyme activity before (x 3) a nd after (monthly x 6 months) administration of terbinafine (250 mg once da ily x 14 days) was evaluated with the dextromethorphan to dextrorphan urina ry metabolite ratios. On each study day a predose urine sample was collecte d, 0.3 mg/kg dextromethorphan was administered, and urine was collected for 24 hours, Dextromethorphan and its metabolites were quantified from urine by HPLC. Results: Baseline phenotype values were concordant with individual genotype . In all extensive metabolizers, the administration of terbinafine resulted in a dramatic increase in the dextromethorphan/dextrorphan ratio, converti ng 4 of the 6 extensive metabolizers into phenotypic poor metabolizers. On average, a 97-fold increase in ratio (range, 35 to 265) was observed for ex tensive metabolizers after the administration of terbinafine. No significan t change was observed in the metabolite ratios of poor metabolizers during the course of the study. Conclusions: Terbinafine inhibits CYP2D6 sufficiently to produce a discorda nce between genotype and phenotype for the enzyme. The dextromethorphan/dex trorphan metabolite ratios increased in all individuals, with otherwise fun ctional CYP2D6 activity. The disposition of CYP2D6 substrates coadministere d with terbinafine may be significantly altered in extensive metabolizers f or this cytochrome P450 isoform, who comprise approximately 93% of the popu lation.