Kinetical analysis of pharmacodynamics based on drug-receptor interactions

1)在分子水平上，强心苷抑制Na^+，K^+-ATP酶，这是一种与钠泵相关的膜结合酶。由于钠泵是维持大多数易兴奋细胞正常静息电位所必需的，因此通常认为洋地黄的毒性至少有一部分是由这种酶抑制作用引起的。这种泵抑制是否是强心苷的正性变力作用（PIA）的原因或只是一种平行现象一直存在争议。通过改变灌注速率，对哇巴因在家兔体内的PIA出现过程进行了动力学分析。用快速过滤法检测了哇巴因与心肌组织匀浆中Na^+，K^+-ATP酶的特异性结合。在体内实验中，以~ 3 H-哇巴因和dp/dt，max作为哇巴因PIA的指标，同时测定了哇巴因的血药浓度（Cp）和PIA。在Cp和 ...更多信息 皮亚此外，PIA的出现过程与哇巴因从血浆室向外周室转移的动力学过程相同。这一过程不能用PIA与单个受体有关的假设来解释，其占据过程是PIA出现的限速步骤。体外结合实验表明，哇巴因与心肌Na^+，K^+-ATP酶的结合是缓慢的，可分为高亲和力和低亲和力两种类型。2）以清醒小鼠脑区3 H-3-O-甲基葡萄糖（M）和14 C-2-脱氧葡萄糖（D）的脑分布为基础，用葡萄糖双标记物模拟法测定了清醒小鼠脑区葡萄糖（G）的利用率，并与正常小鼠比较。静脉注射氯硝西泮（0.01-1.0 mg/kg）后1小时。静脉推注两种化合物（M，D）后，获得血浆（C^M，C^D）和局部脑中示踪剂的时间活性数据。对于皮质，静脉注射D和M后10分钟的表观分布容积（D的V^D，M的V^M）分别为0.64 ± 0.07（ml/g脑）和0.33 ± 0.03（ml/g脑）。在氯硝西泮存在下，磷酸化清除率（CL^D=（V^D-V^M）/θ）显著降低（30%），而集总常数（LC;LC=LC，同位素效应）没有变化。在氯硝西泮存在下，局部脑中的葡萄糖代谢率（rCMRglc=CL^DXC^G/LC）降低（15%）。因此，应该可以清楚地可视化的镇静作用的苯二氮卓类药物对局部脑功能在体内，使用双标记葡萄糖类似物的方法。少

1) At the molecular level, cardiac glycosides inhibit Na^+,K^+-ATPase, a membrane bound enzyme associated with the sodium pump. Since the sodium pump is necessary for maintenance of normal resting potential in most excitable cells, it is generally believed that at least a portion of the toxicity of digitals is caused by this enzyme-inhibiting action. It has been controversial whether this pump inhibition is the cause of positive inotropic action (PIA) of cardiac glycosides or just a parallel phenomenon. We then performed the kinetic analysis of the appearance process of PIA of ouabain in the rabbits by changing infusion rate. We also examined the specific binding of ouabain to Na^+,K^+-ATPase in the cardiac tissue homogenate, using rapid filtration method. In in vivo experiments, we measured the plasma concentration (Cp) and PIA of ouabain simultaneously, using 3H-ouabain and dp/dt, max as an index of PIA. Remarkable infusion rate dependency was found in th relationship between Cp and … More PIA. In addition the appearance process of PIA was kinetically the same as that of ouabain transfer from plasma compartment to peripheral compartment. This process could not be explained by the assumption that PIA is related to the single receptor and its occupation process is the rate limiting step of the appearance of PIA. It was made clear from in vitro binding experiments that the binding of ouabain to cardiac Na^+,K^+-ATPase is slow and classified into two types (high and low affinity). Then it is suggested that infusion rate rate dependet relationship between Cp and PIA may be explained by the model based on the two-receptors.2) Local cerebral glucose (G) utilization was measured, using the double-label glucose analogue method, based on the brain disposition of 3H-3-0-methyl-glucose (M) and 14C-2-deoxy-glucose (D) in the brain region of awake mouse, at 1 hr after i.v. administration of clonazepam (0.01-1.0 mg/kg). After bolus i.v. injection of two compounds (M,D), time activity data of tracers in plasma (C^M,C^D) and regional brain were obtained. For cortex, the apparent volume of distribution (V^D for D, V^M for M), at 10 min after i.v. administration of D and M, were 0.64 0.07 (ml/g brain) and 0.33 0.03 (ml/g brain), respectively. The phosphorylation clearance (CL^D=(V^D-V^M)/theta) significangly decreased (30%) in the presence of clonazepam, whereas the lumped constant (LC;LC=LC , isotope-effect) did not change. The glucose metabolic rate (rCMRglc=CL^DXC^G/LC), in the presence of clonazepam, decreased (15%) in the regional brain. Thus, it should be possible to clearly visualize the sedative effects of benzodiazepine on regional brain function in vivo, using the double-label glucose analogue method. Less