Aoyama T, Yamamoto K, Kotaki H, Sawada Y, Iga T
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, Japan.
Pharm Res. 1997 Nov;14(11):1601-6. doi: 10.1023/a:1012186519946.
The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed.
MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis.
The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (Ki) of MPD for DA reuptake was estimated to be 41.3 +/- 73.8 nM (mean +/- SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model.
The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may by useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.
对大鼠静脉注射甲基苯丙胺（MPD）后的自发活动变化进行药效学分析。
采用微透析法收集血浆中MPD浓度、纹状体透析液中MPD浓度和多巴胺（DA）水平，并分析静脉注射MPD（2、5和10mg/kg剂量）后的自发活动。
MPD从血浆向脑间质液的转运可用线性二室模型表示。透析液中MPD浓度与DA水平之间的顺时针滞后现象可通过考虑细胞外DA进入多巴胺能神经末梢的米氏型再摄取过程及其被细胞外MPD竞争性抑制的药效学模型来解释。MPD对DA再摄取的抑制常数（Ki）估计为41.3±73.8nM（平均值±标准误），经透析回收率校正后与体外值密切一致。透析液中DA水平与自发活动之间的关系通过考虑两种相反作用（运动亢进和刻板行为）的Emax模型表示。高剂量MPD后的双相自发活动-时间曲线可用该模型表示。
所建立的模型能够解释MPD诱导的DA增加耐受性和复杂的自发活动变化，可能对其他DA再摄取抑制剂，如苯丙胺和甲基苯丙胺也有用。
