The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes.

Abstract

1. The enzyme kinetics of dextromethorphan O‐demethylation in liver microsomes from three extensive metabolisers (EM) with respect to CYP2D6 indicated high (Km1 2.2‐9.4 microM) and low (Km2 55.5‐307.3 microM) affinity sites whereas microsomes from two poor metabolisers (PM) indicated a single site (Km 560 and 157 microM). Similar differences were shown for 3‐methoxymorphinan O‐demethylation to 3‐ hydroxymorphinan (Km 6.9‐9.6 microM in EM subjects; Km 307 and 213 microM in PM subjects). 2. Dextromethorphan O‐demethylation was inhibited competitively by quinidine (Ki 0.1 microM), rac‐perhexiline (Ki 0.4 microM), dextropropoxyphene (Ki 6 microM), rac‐methadone (Ki 8 microM), and 3‐methoxymorphinan (Ki 15 microM). These compounds were also potent inhibitors of 3‐methoxymorphinan O‐demethylation with IC50 values ranging from 0.02‐12 microM. 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 (Km 632‐977 microM) and dextrorphan N‐demethylation to 3‐hydroxymorphinan (Km 1571‐4286 microM) 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. 1994 The British Pharmacological Society