Disposition kinetics of the enantiomers of methamphetamine and its metabolites in rats.

Abstract

Methamphetamine (MAP), the N-methyl derivative of amphetamine (AP), has been abused by human populations in several countries. There are stereoisomeric differences in the pharmacodynamics of the enantiomers with the d-enantiomer of both drugs being more potent than the antipode in its central stimulating effects. The stereoisomeric differences in disposition kinetics of MAP and its metabolites were studied in rats. Several sensitive enantiomer-specific HPLC methods were developed to quantitate enantiomers of MAP and its metabolites in serum and urine samples. The optical isomers of these compounds are derivatized by reacting with a chiral fluorescent reagent, (-)-1-(9-fluorenyl)ethyl chloroformate, before separation on a reverse-phase HPLC column. These methods have sensitivities in the low ng/ml range. Both MAP and AP are low protein-bound drugs. There are slight differences in serum protein binding between MAP enantiomers. The binding of d-AP is greater than l-AP. Following administration of racemic MAP to rats, the serum concentration of the d-enantiomer was higher than the l-enantiomer. The metabolites recovered in urine are enantiomers of MAP, AP, p-hydroxymethamphetamine (OHMAP) and p-hydroxyamphetamine (OHAP). A greater amount of the d-enantiomer of MAP and AP could be recovered compared with the l-enantiomer. The hydroxylated metabolites were excreted as unconjugated and conjugated forms with the total l-enantiomer being higher than the antipode. There are stereoisomeric differences for both clearance and volume of distribution of MAP. When racemic AP was administered, AP and unconjugated and conjugated of OHAP could be recovered in urine. Both clearance and volume of distribution of l-AP are significantly higher than d-AP. The clearance of d-OHMAP is greater than that of l-OHMAP. The change in enantiomeric ratio (l-/d-) of metabolites following MAP compared to that following AP suggested the existence of multiple stereoselective pathways involved in the disposition of these compounds. The differences in serum concentrations between AP enantiomers was magnified following racemic MAP, which suggested stereoselective N-demethylation. There are no differences in disposition kinetics of MAP between Sprague-Dawley and Fisher 344 rats. Activated charcoal given orally 10 minute before an iv dose of racemic MAP did not enhance the elimination of the drug in vivo.