PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF THE ACTIONS OF D-AMPHETAMINE AND D-METHAMPHETAMINE ON THE DOPAMINE TERMINAL

To establish whether the actions of D-amphetamine (Amp) and D-methamph etamine (MeAmp) on the striatal dopamine system were equipotent, pharm acokinetic profiles of each drug were applied to an analysis of their respective induced dopamine efflux profiles. Amp or MeAmp (1 and 5 mg/ kg i.v.) was administered to chloral hydrate-anesthetized rats; plasma and brain kinetics were then assessed from 5 to 60 min. Dose-dependen t increases in Amp and MeAmp plasma levels resulted in proportional in creases in striatum levels that were equivalent for both drugs; elimin ation rates also were similar and were characterized by a first-order decay process. After MeAmp administration, low levels of brain MeAmp m etabolites were detected throughout the l-hr time period; relative to MeAmp, Amp and p-hydroxy-MeAmp levels were less than 10 and 1%, respec tively. The drug-induced dopamine efflux profiles in the striatum were characterized by microdialysis; Amp and MeAmp (1, 2.5 and 5 mg/kg i.v .) effected equivalent, dose-dependent increases in extracellular dopa mine levels. For both drugs at 5-and 10-min postinjection, increases i n drug striatum levels preceded increases in dopamine efflux. In contr ast, from the time of the peak dopamine responses observed at 10 to 20 min until the end of the study at 90 min, changes in striatal drug le vels were correlated with extracellular dopamine levels; this correlat ion was similar for both drugs. These results indicate that Amp and Me Amp pharmacokinetics and their subsequent dopamine responses in the st riatum are equivalent. The pharmacokinetic analysis can be extended to the interpretation of other comparative studies that assess effects o f Amp and MeAmp. Accordingly, any differential responses observed betw een Amp and MeAmp will be a function of pharmacodynamic and not pharma cokinetic actions of the two drugs.