In-vivo and in-vitro dextromethorphan metabolism in SD and DA rat : An animal model of the debrisoquine-type polymorphic oxidation in man

Abstract

The female dark Agouti (DA) rat is well established as an animal model for the debrisoquine poor metabolizer phenotype (PM), whereas the SD rat represents the extensive metabolizer (EM). It is not known, however, if the DA rat also is representative for the dextromethorphan (DEM) PM, a compound recently demonstrated to be subjected to the debrisoquine phenotype in man. Studies were performed, therefore, to evaluate in-vivo and in-vitro metabolism of DEM in DA and SD rats. After oral administration of 50 mg/kg of DEM, the DA rat excreted 25 ± 6% of the dose in 72-hr urine as O-demethylated product (dextrorphan), whereas the SD excreted 40 ± 9% (P < 0.002). Metabolic ratio of O-demethylation was 0.46 ± 0.11 in DA and 0.02 ± 0.01 in SD (P < 0.001). As a compensatory mechanism, N-demethylation was ninefold increased in DA compared to SD (8.0 ± 3% of the dose excreted in urine of DA as methoxymorphinan vs 0.9 ± 0.7% in SD) (P < 0.001). Total plasma clearance of DEM was 95 ± 20 ml/min/kg in SD and 45 ± 13 ml/min/kg in DA (P < 0.001). In vitro, microsomal affinity for DEM O-demethylation was > 50 times higher in SD than in DA rats (P < 0.004), whereas V max, did not differ statistically. V max for N-demethylation was 80% increased in DA (P < 0.01), whereas corresponding K m values did not differ. It appears that the differences in DEM metabolism between DA and SD rats are qualitatively similar to human EM and PM phenotypes, respectively. Whether this is also true for the underlying mechanism(s) however, remains to be resolved.