In vitro metabolism of amphetamine: an apparent enantiomeric interaction

The stereoselective formation of the major metabolites N-hydroxyamphetamine and 1-phenyl-2-propanol in incubations of amphetamine with 9,000 X g supernatant fractions of rabbit liver has been studied using deuterium labelling in conjunction with selected-ion-monitoring gas chromatography/mass spectrometry. Comparison of separate incubations of (R)-amphetamine with those of (S)-amphetamine-d3 and of (S)-amphetamine with those of (R)-amphetamine-d3 showed that larger amounts of the two metabolites were formed from the (R) enantiomer. When "pseudoracemic" mixture (R)-amphetamine/(S)-amphetamine-d3 or (R)-amphetamine-d3/(S)-amphetamine were incubated the two metabolites were preferentially formed from the (S) enantiomer. Studies on the disappearance of substrate during incubation gave results in agreement with the findings on stereoselective metabolite formation. It was concluded that (S)-amphetamine or one of its metabolites inhibits the metabolism of the (R) enantiomer.