Dextromethorphan metabolism in rat: Interstrain differences and the fate of individually administered oxidative metabolites

1. Dextromethorphan undergoes O- and N-demethylation, with the resultant metabolites being further N- and O-demethylated respectively to 3-hydroxymorphinan. The polymorphically expressed O-demethylation reaction is catalysed by P4502D1 in the Sprague-Dawley (SD) rat. The Dark-Agouti (DA) rat lacks this enzyme. 2. The aims were: (1) to determine if there were strain differences also in the Hooded Wistar (HW) and Albino Wistar (AW) rats with respect to the four demethylation reactions after dextromethorphan 20 mg/kg intraperitoneally; (2) to investigate the inhibition of the demethylation reactions by quinine and quinidine (each 40 mg/kg i.p.) in the above strains; and (3) to investigate the fate of separately administered metabolites (5 mg/kg i.p.) of dextromethorphan in the SD strain. 3. The total recovery of dextromethorphan and metabolites in the four strains ranged from 38 to 64% of the dose. The O-demethylation ratios (expressed as the ratio of urinary total dextrorphan divided by dextromethorphan) in the AW and DA strains were similar but less than in the SD/HW strains; the N-demethylation ratios (expressed as the ratio of urinary total 3-hydroxymorphinan plus 3-methoxymorphinan divided by dextromethorphan) in the DA and SD strains were similar but greater than in the AW and HW strains. Quinine and quinidine significantly reduced the O-demethylation ratio in the SD and DA rat strains, and the N-demethylation ratio in the SD strain. 4. In the SD rat the major metabolic route was via O-demethylation to dextrorphan. The source of 3-hydroxymorphinan is primarily from N-demethylation of dextromethorphan to 3-methoxymorphinan and its subsequent O-demethylation to 3-hydroxymorphinan. The O-demethylation metabolic ratio for dextromethorphan should be calculated as the quotient of urinary total dextrorphan divided by dextromethorphan.