THE ROLE OF CYP2D6 IN PRIMARY AND SECONDARY OXIDATIVE-METABOLISM OF DEXTROMETHORPHAN - IN-VITRO STUDIES USING HUMAN LIVER-MICROSOMES

1 The enzyme kinetics of dextromethorphan O-demethylation in liver microsomes from three extensive metabolisers (EM) with respect to CYP2D6 indicated high (K-m1 2.2-9.4 mu M) and low (K-m2 55.5-307.3 mu M) affinity sites whereas microsomes from two poor metabolisers (PM) indicated a single site (K-m 560 and 157 mu M). Similar differences were shown for 3-methoxymorphinan O-demethylation to 3-hydroxymorphinan (K-m 6.9-9.6 mu M in EM subjects; K-m 307 and 213 mu M in PM subjects). 2 Dextromethorphan O-demethylation was inhibited competitively by quinidine (K-i 0.1 mu M), rac-perhexiline (K-i 0.4 mu M), dextropropoxyphene (K-i 6 mu M), rac-methadone (K-i 8 mu M), and 3-methoxymorphinan (K-i 15 mu M). These compounds were also potent inhibitors of 3-methoxymorphinan O-demethylation with IC50 values ranging from 0.02-12 mu M. Anti-LKM1 serum inhibited both dextromethorphan and 3-methoxymorphinan O-demethylations in a titre-dependent manner. 3 The Michaelis-Menten constant for dextromethorphan N-demethylation to 3-methoxymorphinan (K-m 632-977 mu M) and dextrorphan N-demethylation to 3-hydroxymorphinan (K-m 1571-4286 mu M) did not differ between EM and PM microsomes. These N-demethylation reactions were not inhibited by quinidine and rac-methadone or LKM1 antibodies. 4 Dextromethorphan and 3-methoxymorphinan are metabolised by the same P450 isoform, CYP2D6, whereas the N-demethylation reactions are not carried out by CYP2D6.