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.

[1]  C. Funck-Brentano,et al.  CYP2D6- and CYP3A-dependent metabolism of dextromethorphan in humans. , 1993, Pharmacogenetics.

[2]  A. Somogyi,et al.  Primary and secondary oxidative metabolism of dextromethorphan. In vitro studies with female Sprague-Dawley and Dark Agouti rat liver microsomes. , 1993, Biochemical pharmacology.

[3]  A. Malick,et al.  Nasal delivery of [14C]dextromethorphan hydrochloride in rats: levels in plasma and brain. , 1992, Journal of pharmaceutical sciences.

[4]  M. Eichelbaum,et al.  Thebaine O-demethylation to oripavine: genetic differences between two rat strains. , 1991, Xenobiotica; the fate of foreign compounds in biological systems.

[5]  M. Eichelbaum,et al.  Codeine O-demethylation: rat strain differences and the effects of inhibitors. , 1991, Biochemical pharmacology.

[6]  A. Somogyi,et al.  Simultaneous Determination of Dextromethorphan and Three Metabolites in Plasma and Urine Using High‐Performance Liquid Chromatography with Application to Their Disposition in Man , 1990, Therapeutic drug monitoring.

[7]  U. Meyer,et al.  The CYP2D gene subfamily: analysis of the molecular basis of the debrisoquine 4-hydroxylase deficiency in DA rats. , 1989, Biochemistry.

[8]  A. Boobis,et al.  The specificity of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in the rat is the inverse of that in man. , 1989, Biochemical pharmacology.

[9]  A. Koster,et al.  Comparison of microsomal drug-metabolizing enzymes in 14 rat inbred strains. , 1989, Biochemical pharmacology.

[10]  T. Zysset,et al.  In-vivo and in-vitro dextromethorphan metabolism in SD and DA rat. An animal model of the debrisoquine-type polymorphic oxidation in man. , 1988, Biochemical pharmacology.

[11]  G. Labbe,et al.  Polymorphism of dextromethorphan oxidation in a French population. , 1987, British journal of clinical pharmacology.

[12]  F. Guengerich,et al.  Oxidation of quinidine by human liver cytochrome P-450. , 1986, Molecular pharmacology.

[13]  A. Boobis,et al.  Bufuralol 1'-hydroxylase activity of the rat. Strain differences and the effects of inhibitors. , 1986, Biochemical pharmacology.

[14]  G. Pfaff,et al.  Pharmacogenetics of dextromethorphan O-demethylation in man. , 1986, Xenobiotica; the fate of foreign compounds in biological systems.

[15]  J. Bircher,et al.  Polymorphic dextromethorphan metabolism: Co‐segregation of oxidative O‐demethylation with debrisoquin hydroxylation , 1985, Clinical pharmacology and therapeutics.

[16]  G. Pfaff,et al.  Inter-individual variation in the metabolism of dextromethorphan , 1983 .

[17]  J. Idle,et al.  Animal modelling of human polymorphic drug oxidation—the metabolism of debrisoquine and phenacetin in rat inbred strains , 1981, The Journal of pharmacy and pharmacology.

[18]  J. W. Barnhart.  The urinary excretion of dextromethorphan and three metabolites in dogs and humans. , 1980, Toxicology and applied pharmacology.

[19]  D. Parke.  The biochemistry of foreign compounds , 1968 .

[20]  A. Taddeo,et al.  Metabolism and excretion of tritiated dextromethorphan by the rat. , 1967, The Journal of pharmacology and experimental therapeutics.