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首页> 外文期刊>Biological & pharmaceutical bulletin >Pharmacokinetic and Pharmacodynamlc Studies of Chlorpromazine in Rats: Effect of Chlorpromazine on Dopamine and Dopamine Metabolite Concentration in Rat Striatum
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Pharmacokinetic and Pharmacodynamlc Studies of Chlorpromazine in Rats: Effect of Chlorpromazine on Dopamine and Dopamine Metabolite Concentration in Rat Striatum

机译：氯丙嗪在大鼠体内的药代动力学和药代动力学研究：氯丙嗪对大鼠纹状体中多巴胺和多巴胺代谢产物浓度的影响

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The concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum were increased after the i.v. administration of chlorpromazine (CPZ). Assuming that the enhancement of dopamine concentration in the striatum after CPZ administration is caused by the release of dopamine from the dopamine neuronal terminals, the relationship between the enhancement of dopamine concentration in the striatum and CPZ concentration in the cerebrospinal fluid (CSF) and the striatum were analyzed using the sigmoid EmaK model. The enhancement of dopamine concentration in the striatum could be described quantitatively by this model. The time courses of DOPAC and HVA concentration in the striatum after CPZ administration were analyzed using the dopamine metabolism model, which has an apparent first-order clearance from dopamine to DOPAC and HVA, and also using the Michaelis-Menten type elimination kinetics of DOPAC and HVA. The values of the metabolism parameters for DOPAC and HVA were fixed to the estimated values of the L-dopa study. The calculated values of DOPAC and HVA concentrations in the striatum were greater than those of the observed data. The elimination parameters for DOPAC and HVA were reestimated by the nonlinear least squares method. The time courses of DOPAC and HVA concentration in the striatum could be described using these reestimated elimination parameters. These results indicated that the turnover rate of dopamine and dopamine metabolites, DOPAC and HVA in the striatum after CPZ administration is different from that after L-dopa administration. Thus, analysis using the dopamine metabolism model is a useful method not only for the quantitative explanation of the relationship between the CPZ concentration and the enlargement of dopamine concentration in the striatum, but also for the examination of the effect of CPZ on the turnover rate of dopamine and dopamine metabolites, DOPAC and HVA in the striatum.
机译：静脉注射后，大鼠纹状体中多巴胺，3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）的浓度增加。氯丙嗪（CPZ）的管理。假定CPZ给药后纹状体中多巴胺浓度的增加是由于多巴胺从神经元末端释放多巴胺引起的，其与脑脊液（CSF）和纹状体中CPZ浓度的增加之间的关系使用乙状结肠EmaK模型进行分析。该模型可以定量描述纹状体中多巴胺浓度的增加。使用多巴胺代谢模型分析了CPZ给药后纹状体中DOPAC和HVA浓度的时程，该模型具有从多巴胺到DOPAC和HVA的明显一阶清除率，还使用了DOPAC和HVA。 DOPAC和HVA的代谢参数值固定为L-多巴研究的估计值。纹状体中DOPAC和HVA浓度的计算值大于观察到的数据。通过非线性最小二乘法重新估计DOPAC和HVA的消除参数。使用这些重新估计的消除参数可以描述纹状体中DOPAC和HVA浓度的时程。这些结果表明，CPZ给药后纹状体中多巴胺和多巴胺代谢产物，DOPAC和HVA的周转率与L-多巴给药后不同。因此，使用多巴胺代谢模型进行分析不仅是定量解释纹状体中CPZ浓度与多巴胺浓度增大之间关系的有用方法，而且还可以用于检验CPZ对CZ转换率的影响。多巴胺和多巴胺代谢产物，纹状体中的DOPAC和HVA。

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