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 less than 0.002). Metabolic ratio of O-demethylation was 0.46 +/- 0.11 in DA and 0.02 +/- 0.01 in SD (P less than 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 less than 0.001). Total plasma clearance of DEM was 95 +/- 20 ml/min/kg in SD and 45 +/- 13 ml/min/kg in DA (P less than 0.001). In vitro, microsomal affinity for DEM O-demethylation was greater than 50 times higher in SD than in DA rats (P less than 0.004), whereas Vmax did not differ statistically. Vmax for N-demethylation was 80% increased in DA (P less than 0.01), whereas corresponding Km 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.