Studies on chiral interactions of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane and the corresponding N-hydroxy metabolites with cytochrome P-450.

The stereoselective pharmacological behavior and metabolism of the potent psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane have led to an investigation of the interactions of the racemic amine, its enantiomers, and the corresponding N-hydroxy metabolites with rabbit liver microsomal cytochrome P-450. An examination of the formation of cytochrome P-450 metabolic intermediate complexes with these species suggests that N-oxidation of the pharmacologically active (R)-amine in inhibited by the S enantiomer. Additionally, metabolic intermediate complex formation [favored by the (R)-amine] appears to be associated with loss of microsomal mixed function N-oxidase activity. The results have led to the prediction that N-hydroxylation of pure (R)-amine may be a qualitatively more important pathway than that observed with racemic amine even though this biotransformation may be suicidal.

In vitro stereoselective metabolism of the psychotomimetic amine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane. An apparent enantiomeric interaction.

The stereoselective metabolism [R/S (metabolized) less than 1] of the psychotomimetic amine (R,S)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane in 10 000g rabbit liver homogenate supernatant and 100 000g microsomal fractions has been demonstrated with the aid of the chiral reagent (S)-N-pentafluorobenzoylprolyl-1-imidazolide and GLC analyses. In contrast to the enantiomeric discrimination observed with racemic amine, the individual isomers were metabolized at approximately the same rate. This apparent enantiomeric interaction illustrates the fact that racemates should be viewed as unique chemical species with pharmacodynamic and toxicologic profiles potentially different from the individual antipodes.