Pharmacokinetic and Pharmacodynamic Studies of L-Dopa in Rats. II. Effect of L-Dopa on Dopamine and Dopamine Metabolite Concentration in Rat Striatum

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The purpose of this investigation was to quantitatively describe the time courses of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations in the striatum after L-dopa injection using a constructed dopamine metabolism model. The time courses of dopamine, DOPAC and HVA concentration in the striatum of rats was determined before and after the rapid i. v. injection of 10,50 and 100mg/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±0.7μg, 3.6±0.4μg and 1.0±0.2μg/g, respectively. The dopamine concentration in the striatum increased immediately after L-dopa injection, with the peak concentration (15.9±0.5μg/g) occurring at 3 min ; then it returned to the pre-medication level until 2h at 100mg/kg dosing. The time course of dopamine concentration in the striatum was analyzed on a constructed dopamine metabolism model which has a zero-order production rate for the production of dopamine (i.e. release from the dopamine neuronal terminals) and two apparent first-order clearance terms, one from L-dopa to dopamine, which was estimated in the previous report, and the other from dopamine to dopamine metabolites (DOPAC and HVA). However, the time course of dopamine concentration in the striatum could not be described by this model. Since the effect of L-dopa on the enlargement of dopamine concentration is known to be attributable to the endogenously released dopamine from the dopamine neuronal terminals, the time course of dopamine concentration in the striatum after L-dopa injection was analyzed on 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 dopamine but also by the endogenously released dopamine from dopamine neuronal terminals. The result indicated that the effect of L-dopa on the enlargement of dopamine concentration could be described quantitatively by these assumptions. The DOPAC and HVA concentrations in the striatum also increased gradually after L-dopa injection, with the peak concentration (15.6±2.0 and 6.6±0.3μg/g) occurring at 20 and 90 min, and they then returned to the control level until 4 and 6h, respectively, at 100mg/kg dosing. The time course of DOPAC and HVA concentration in the striatum could be reasonably well described by a constructed dopamine metabolism model which has an apparent first-order clearance from dopamine to DOPAC and HVA, and Michaelis-Menten type elimination kinetics of DOPAC and HVA. Thus, it was clarified that the time courses of dopamine, DOPAC and HVA concentration in rat striatum after the i.v. injection of L-dopa can be explained using the dopamine metabolism model. This dopamine metabolism model might be able to be used for the pharmacokinetic-pharmacodynamic analysis of dopaminergic acting drugs.
社団法人日本薬学会の論文
1994-12-15

Pharmacokinetic and Pharmacodynamic Studies of L-Dopa in Rats. II. Effect of L-Dopa on Dopamine and Dopamine Metabolite Concentration in Rat Striatum

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