Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (1999) 65, 465–472; doi:
Investigation of terbinafine as a CYP2D6 inhibitor in vivo*
Susan M. Abdel-Rahman PharmD1, R. Russell Gotschall MS1, Ralph E. Kauffman MD1, J. Steven Leeder PharmD, PhD1 and Gregory L. Kearns PharmD1
1Section of Pediatric Clinical Pharmacology and Experimental Therapeutics, Children's Mercy Hospital, and the Departments of Pediatrics, Pharmacy Practice, Pharmacology, and Pharmaceutical Sciences, University of Missouri–Kansas City, Kansas City, Mo
Correspondence: Susan M. Abdel-Rahman, PharmD, Section of Pediatric Clinical Pharmacology and Experimental Therapeutics, The Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108. E-mail: srahman@cmh.edu
*Supported in part by grant 1U01 HD 31313-06 (Network of Pediatric Pharmacology Research Units) from the National Institute of Child Health and Human Development, Bethesda, Md.
Received 11 November 1998; Accepted 23 December 1998.
Abstract
Background: Terbinafine is an orally active antifungal used in the treatment 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 finding that terbinafine may inhibit CYP2D6.
Methods: Nine healthy volunteers were enrolled in this study—6 genotypically consistent with an extensive metabolizer phenotype and 3 genotypic poor metabolizers for CYP2D6. The change in CYP2D6 enzyme activity before (
3) and after (monthly 6 months) administration of terbinafine (250 mg once daily 14 days) was evaluated with the dextromethorphan to dextrorphan urinary metabolite ratios. On each study day a predose urine sample was collected, 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, converting 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 extensive metabolizers after the administration of terbinafine. No significant change was observed in the metabolite ratios of poor metabolizers during the course of the study.
Conclusions: Terbinafine inhibits CYP2D6 sufficiently to produce a discordance between genotype and phenotype for the enzyme. The dextromethorphan/dextrorphan metabolite ratios increased in all individuals, with otherwise functional CYP2D6 activity. The disposition of CYP2D6 substrates coadministered with terbinafine may be significantly altered in extensive metabolizers for this cytochrome P450 isoform, who comprise approximately 93% of the population.
