Dextromethorphan metabolism in Jordanians: dissociation of dextromethorphan O-demethylation from debrisoquine 4-hydroxylation.

Abstract

The concentrations of dextromethorphan (DM) and its metabolites dextrorphan (DRP), 3-methoxymorphinan (MM) and 3-hydroxymorphinan (HM) were measured in 8 h urine samples from 266 unrelated healthy Jordanian subjects following oral administration of 30 mg dextromethorphan hydrobromide and using a rapid, sensitive and precise HPLC method with fluorometric detection. The frequency of the 'poor' metabolizer status of DM-O-demethylation as judged by log DM/DRP was found to be 6.8% with a 95% confidence interval of 3.8-9.8%. There was a strong correlation between log DM/DRP and log total non-O-demethylated compounds (NODM)/total O-demethylated metabolites (ODM) metabolic ratios (r = 0.96, P < 0.01). However, one subject with log DM/DRP of 0.05 that classifies him as a poor metabolizer was found to have a log NODM/ODM of -0.73 which is in the range of extensive metabolizer status suggesting the presence of another cytochrome P450 isoenzyme involved in dextromethorphan O-demethylation. Dextromethorphan N-demethylation to 3-methoxymorphinan was detected in 55.3% of individuals. Furthermore, a dissociation between dextromethorphan O-demethylation and debrisoquine (D) 4-hydroxylation has been observed. Among the 116 subjects phenotyped with both dextromethorphan and debrisoquine, 7 were poor metabolizers of both, three were poor metabolizers of debrisoquine and extensive metabolizers of dextromethorphan whilst 4 were poor metabolizers of dextromethorphan and extensive metabolizers of debrisoquine, one of whom was reclassified as an extensive metabolizer of dextromethorphan using log NODM/ODM to characterize dextromethorphan metabolizer status.