Disposition kinetics of d- and l-amphetamine following intravenous administration of racemic amphetamine to rats.

Amphetamine (AP), a chiral drug, displays stereoselective differences in biological action. The effect of stereochemistry on the disposition kinetics of the enantiomers has not been thoroughly studied. We examined the disposition kinetics of AP in rats using a sensitive precolumn derivatization HPLC method that can separate the enantiomers of AP and its metabolites. Male Sprague-Dawley rats were given a short intravenous infusion of racemic AP (15 mg/kg). The systemic and renal clearances, steady-state volume of distribution, and terminal half-life for l-AP were (mean +/- SD), respectively: 65.6 +/- 9.25 ml/min.kg; 15.4 +/- 2.55 ml/min.kg; 4.33 +/- 0.71 liters/kg; and 0.96 +/- 0.13 hr. The corresponding values for d-AP were: 50.8 +/- 6.88 ml/min.kg; 12.5 +/- 2.02 ml/min.kg; 3.84 +/- 0.55 liters/kg; and 1.12 +/- 0.09 hr. There are statistically significant differences between the enantiomers in all pharmacokinetic parameters except half-life. About 40% of the l-AP dose was excreted in urine as l-p-hydroxyamphetamine and 24% as intact drug. The corresponding values for d-AP were 32% and 26%, respectively. p-Hydroxyamphetamine was primarily excreted into urine as the conjugated form. These data indicate stereoselective differences in the pharmacokinetics of the enantiomers of AP after administration of racemic drug in the rat.