Terbinafine and potential drug interactions

Abstract

The article by Gupta, Katz, and Shear provides an excellent overview of drug interactions with systemic antifungal agents but may be falsely reassuring in light of more recent information (J Am Acad Dermatol 1999;41:237-49). Although the article states that terbinafine “may cause a weak induction of CYP [cytochrome P-450] isoforms,” a recent article has demonstrated significant inhibition (between 35- and 265-fold) of the hepatic cytochrome isoform 2D6 (CYP2D6).1Abdel-Rahman SM, Gotschall RR, Kauffman RE, Leeder JS, Kearns GL. Investigation of terbinafine as a CYP2D6 inhibitor in vivo. Clin Pharmacol Ther 199;65:465-72.Google Scholar Because 93% of the population are extensive metabolizers for CYP2D6, drugs metabolized by this pathway could be significantly affected. More than 35 drugs have been identified as undergoing biotrans-formation with this cytochrome.2Abdel-Rahman SM Marcucci K Boge T Gotschall RR Kearns GL Leeder JS Potent inhibition of cytochrome P-450 2D6-mediated dextromethorphan O-demethylation by terbinafine.Drug Metab Dispos. 1999; 27: 770-775PubMed Google Scholar Some of the drugs metabolized by CYP2D6 include selective serotonin reuptake inhibitors, oxycodone, antipsychotics, metoprolol, classic H1 antihistamines, quinidine, viral protease inhibitors, and nortriptyline.3Ozminkowski RJ Hylan TR Melfi CA Meneades LM Crown WH Croghan TW et al.Economic consequences of selective serotonin reuptake inhibitor use with drugs also metabolized by the cytochrome P-450 system.Clin Ther. 1998; 20: 780-796Abstract Full Text PDF PubMed Scopus (8) Google Scholar, 4Heiskanen T Olkkola KT Kalso E Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.Clin Pharmacol Ther. 1998; 64: 603-611Crossref PubMed Scopus (212) Google Scholar, 5Fang J Gorrod JW Metabolism, pharmacogenetics, and metabolic drug-grug interactions of antipsychotic drugs.Cell Mol Neurobiol. 1999; 19: 491-510Crossref PubMed Scopus (45) Google Scholar, 6Huang J Chuang SK Cheng CL Lai ML Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes.Clin Pharmacol Ther. 1999; 65: 402-407Crossref PubMed Scopus (62) Google Scholar, 7Hamelin BA Bouayad A Drolet B Gravel A Turgeon J In vitro characterization of cytochrome P450 2D6 inhibition by classic H1 receptor antagonists.Drug Metab Dispos. 1998; 26: 536-539PubMed Google Scholar, 8von Moltke LL Greenblatt DJ Duan SX Daily JP Harmatz JS Shader RI Inhibition of desipramine hydroxylation (Cytochrome P450 2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo.J Pharm Sci. 1998; 87: 84-89Crossref Scopus (76) Google Scholar, 9Venkatakrishnan K von Moltke LL Greenblatt DJ Nortriptyline E-10-hydroxylation in vitro by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs.J Clin Pharmacol. 1999; 39: 567-577Crossref PubMed Scopus (88) Google Scholar One recent study found a greater than threefold increase of extrapyramidal side effects in CYP2D6-impaired patients.10Vandel P Haffen E Vandel S Bonin B Nezelof S Sechter D et al.Drug extrapyramidal side effects: CYP2D6 genotypes and phenotypes.Eur J Clin Pharmacol. 1999; 55: 659-665Crossref PubMed Scopus (56) Google Scholar With terbinafine's long half-life of 3 weeks, cytochrome inhibition could take several weeks to resolve.11Nedelman JR Gibiansky E Robbins BA Cramer JA Riefler JF Meligeni JA Pharmacokinetics and pharmacodynamics of multiple-dose terbinafine.J Clin Pharmacol. 1996; 36: 452-461Crossref PubMed Scopus (26) Google Scholar Caution should be used when prescribing terbinafine in the presence of drugs using the CYP2D6 pathway until the impact of this inhibition is fully elucidated.