Polymorphic dextromethorphan metabolism: Co-segregation of oxidative O-demethylation with debrisoquin hydroxylation

Abstract

Dextromethorphan hydrobromide, 25 mg po, was given to 268 unrelated Swiss subjects to study urinary drug and metabolite profiles. Rates of O-demethylation yielding the main metabolite dextrorphan were expressed by the urinary dextromethorphan/dextrorphan metabolic ratio. We found a bimodal distribution of this parameter in our population study, which indicates that there are two phenotypes for dextromethorphan O-demethylation. The antimode at a metabolic ratio of 0.3 separated the poor metabolizer (PM; n = 23; prevalence of 9%) from extensive metabolizer (EM) phenotypes. Urinary output of dextrorphan was less than 6% of the dose in all PMs and was 50% in the 245 EMs. Pedigree analysis of 14 family studies revealed an autosomal-recessive transmission of deficient dextromethorphan O-demethylation. In these families, 37 heterozygous genotypes could be identified; however, through use of the urinary drug and metabolite analysis it was not possible to identify the heterozygous genotypes within the EM phenotype group. Co-segregation of dextromethorphan O-demethylation with debrisoquin 4-hydroxylation was also studied. Complete concordance of the two phenotypic assignments was obtained, with a Spearman rank correlation coefficient of rs = 0.78 (n = 62; P less than 0.0001) for dextromethorphan and debrisoquin metabolic ratios. Presumably the two drug oxidation polymorphisms are under the same genetic control. Thus the innocuousness and ubiquitous availability of dextromethorphan render it attractive for worldwide pharmacogenetic investigations in man.

Extensive oxidative metabolism of dextromethorphan in patients with almitrine neuropathy.

“…The rate of O-demethylation of dextromethorphan to dextrorphan, its main metabolite, is highly correlated with that of debrisoquine 4-hydroxylation (Kupfer et al, 1984). Drug oxidation phenotyping with dextromethorphan is in complete concordance with results of phenotyping with debrisoquine (Schmid et al, 1985). Dextromethorphan, an antitussive drug, has the advantages over debrisoquine of being ubiquitously available and innocuous (Schmid et al, 1985;Larrey et al, 1987).…”

“…Drug oxidation phenotyping with dextromethorphan is in complete concordance with results of phenotyping with debrisoquine (Schmid et al, 1985). Dextromethorphan, an antitussive drug, has the advantages over debrisoquine of being ubiquitously available and innocuous (Schmid et al, 1985;Larrey et al, 1987).…”

“…Subjects with a MR above 0.3 were assigned as having the poor metabolizer phenotype and subjects with a MR below 0.3 as having the extensive metabolizer phenotype (Schmid et al, 1985;Larrey et al, 1987).…”

“…Oxidator phenotyping was performed using dextromethorphan as described recently (Schmid et al, 1985;Larrey et al, 1987). The rate of O-demethylation of dextromethorphan to dextrorphan, its main metabolite, is highly correlated with that of debrisoquine 4-hydroxylation (Kupfer et al, 1984).…”

Differential foetal development of the O‐ and N‐demethylation of codeine and dextromethorphan in man.

“…Dextromethorphan has received much attention as a model drug for the common genetic polymorphism of drug oxidation known as the debrisoquine/sparteine type polymorphism ( Eichelbaum, 1984;Idle & Smith, 1979;Schmidt et al, 1985). This monogenically inherited deficiency relates to the metabolism of several drugs in wide clinical use such as ,-adrenoceptor antagonists, antiarrhythmics and antidepressants (Brosen & Gram, 1989).…”