Potent inhibition of cytochrome P-450 2D6-mediated dextromethorphan O-demethylation by terbinafine

Cytochrome P-450 (CYP) 2D6 is responsible for the biotransformation of over 35 pharmacologic agents. In the process of studying CYP2D6 we identified p henotype-genotype discordance In two individuals receiving terbinafine. Thi s prompted evaluation of the potential for terbinafine to inhibit CYP2D6 in vitro. Human hepatic microsomes and heterologously expressed CYP2D6 were i ncubated with terbinafine or quinidine and the formation of dextrorphan fro m dextromethorphan was determined by HPLC. Additionally, preliminary confor mational analyses were conducted to determine the fit of terbinafine Into a previously described pharmacophore model for CYP2D6 inhibitors. The appare nt K-m and V-max of dextrorphan formation from four human hepatic microsome samples ranged from 5.8 to 6.8 mu M and from 172 to 300 pmol/min/mg protei n, respectively. Values of K-m and V-max in the heterologously expressed CY P2D6 system averaged 6.5 +/- 2.1 mu M and 1342 +/- 147 pmol/min/mg protein, respectively. Terbinafine inhibited dextromethorphan O-demethylation with an apparent K-i ranging from 28 to 44 nM in human hepatic microsomes and av eraging 22.4 +/- 0.6 nM for the heterologously expressed enzymes. Results o f quinidine in these systems produced values for K-i ranging from 18 to 43 nM, Such strong inhibition of CYP2D6 by terbinafine would not have been pre dicted by the previously proposed pharmacophore model of CYP2D6 inhibitors based on molecular structure. Terbinafine is a potent inhibitor of CYP2D6 w ith apparent K-i values well below plasma and tissue concentrations typical ly achieved during a therapeutic course. This agent needs to be evaluated i n vivo to determine the impact of CYP2D6 inhibition by terbinafine on the m etabolism of concomitantly administered CYP2D6 substrates.