PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF L-DOPA IN RATS .2. EFFECT OF L-DOPA ON DOPAMINE AND DOPAMINE METABOLITE CONCENTRATION IN RATSTRIATUM

The purpose of this investigation was to quantitatively describe the t ime courses of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and ho movanillic acid (HVA) concentrations in the striatum after L-dopa inje ction using a constructed dopamine metabolism model. The time courses of dopamine, DOPAC and HVA concentration in the striatum of rats was d etermined before and after the rapid i.v. injection of 10, 50 and 100 mg/kg using the same animals as in the previous report. The endogenous dopamine, DOPAC and HVA concentrations in the striatum before L-dopa administration were 5.9+/-0.7 mu g, 3.6+/-0.4 mu g and 1.0+/-0.2 mu g/ g, respectively. The dopamine concentration in the striatum increased immediately after L-dopa injection, with the peak concentration (15.9/-0.5 mu g/g) occurring at 3 min; then it returned to the pre-medicati on level until 2 h at 100 mg/kg dosing. The time course of dopamine co ncentration in the striatum was analyzed on a constructed dopamine met abolism model which has a zero-order production rate for the productio n of dopamine (i.e. release from the dopamine neuronal terminals) and two apparent first-order clearance terms, one from L-dopa to dopamine, which,vas estimated in the previous report, and the other from dopami ne to dopamine metabolites (DOPAC and HVA). However, the time course o f dopamine concentration in the striatum could not be described by thi s model. Since the effect of L-dopa on the enlargement of dopamine con centration is known to be attributable to the endogenously released do pamine from the dopamine neuronal terminals, the time course of dopami ne concentration in the striatum after L-dopa injection was analyzed o n the assumption that the effect of L-dopa on the increase of dopamine concentration is caused not only by the metabolism from L-dopa to dop amine but also by the endogenously released dopamine from dopamine neu ronal terminals. The result indicated that the effect of L-dopa on the enlargement of dopamine concentration could be described quantitative ly by these assumptions. The DOPAC and HVA concentrations in the stria tum also increased gradually after L-dopa injection, with the peak con centration (15.6+/-2.0 and 6.6+/-0.3 mu g/g) occurring at 20 and 90 mi n, and they then returned to the control level until 4 and 6 h, respec tively, at 100 mg/kg dosing. The time course of DOPAC and HVA concentr ation in the striatum could be reasonably well described by a construc ted dopamine metabolism model which has an apparent first-order cleara nce from dopamine to DOPAC and HVA, and Michaelis-Menten type eliminat ion kinetics of DOPAC and HVA. Thus, it was clarified that the time co urses of dopamine, DOPAC and HVA concentration in rat striatum after t he i.v. injection of L-dopa can be explained using the dopamine metabo lism model. This dopamine metabolism model might be able to be used fo r the pharmacokinetic-pharmacodynamic analysis of dopaminergic acting drugs.