PT  - JOURNAL ARTICLE
AU  - Alison E. M. Vickers
AU  - John R. Sinclair
AU  - Markus Zollinger
AU  - Francis Heitz
AU  - Ulrike Glänzel
AU  - Laurie Johanson
AU  - Volker Fischer
TI  - Multiple Cytochrome P-450s Involved in the Metabolism of Terbinafine Suggest a Limited Potential for Drug-Drug Interactions
DP  - 1999 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1029--1038
VI  - 27
IP  - 9
4099  - http://dmd.aspetjournals.org/content/27/9/1029.short
4100  - http://dmd.aspetjournals.org/content/27/9/1029.full
SO  - Drug Metab Dispos1999 Sep 01; 27
AB  - Biotransformation pathways and the potential for drug-drug interactions of the orally active antifungal terbinafine were characterized using human liver microsomes and recombinant human cytochrome P-450s (CYPs). The terbinafine metabolites represented four major pathways: 1) N-demethylation, 2) deamination, 3) alkyl side chain oxidation, and 4) dihydrodiol formation. Michaelis-Menten kinetics for the pathways revealed meanKm values ranging from 4.4 to 27.8 μM, andVmax values of 9.8 to 82 nmol/h/mg protein. At least seven CYP enzymes are involved in terbinafine metabolism. Recombinant human CYPs predict that CYP2C9, CYP1A2, and CYP3A4 are the most important for total metabolism. N-demethylation is primarily mediated by CYP2C9, CYP2C8, and CYP1A2; dihydrodiol formation by CYP2C9 and CYP1A2; deamination by CYP3A4; and side chain oxidation equally by CYP1A2, CYP2C8, CYP2C9, and CYP2C19. Additionally, characteristic CYP substrates inhibited pathways of terbinafine metabolite formation, confirming the involvement of multiple enzymes. The deamination pathway was mainly inhibited by CYP3A inhibitors, including troleandomycin and azole antifungals. Dihydrodiol formation was inhibited by the CYP1A2 inhibitor furafylline. Terbinafine had little or no effect on the metabolism of many characteristic CYP substrates. Terbinafine, however, is a competitive inhibitor of the CYP2D6 reaction, dextromethorphan O-demethylation (Ki = 0.03 μM). In summary, terbinafine is metabolized by at least seven CYPs. The potential for terbinafine interaction with other drugs is predicted to be insignificant with the exception that it may inhibit the metabolism of CYP2D6 substrates. Clinical trials are needed to assess the relevance of these findings. The American Society for Pharmacology and Experimental Therapeutics