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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Characterization of pharmacodynamic recession slopes for direct and indirect response models.
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Characterization of pharmacodynamic recession slopes for direct and indirect response models.

机译：直接和间接反应模型的药效学衰退斜率的表征。

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Direct pharmacologic effects are known to recede over time with largely linear slopes (Levy's k.m product, J. Pharm. Sci. 53:342, 1964) and indirect responses have similar behavior. Pharmacodynamic slope properties were examined mathematically for the Hill function with monoexponential drug disposition and simulations were carried out for other pharmacokinetic functions. Both types of pharmacodynamic profiles exhibit a single terminal inflection point (fp) when drug concentrations exceed the EC50 (that concentration causing one-half maximum effect, Emax). For direct effects it was found that Cfp (the drug concentration at fp) = EC50, the determinants of inflection time were identified, and Slopefp = -lambda z gamma Emax/4 where lambda z is the terminal disposition slope and gamma is the Hill coefficient. These characteristics were explored for the four basic indirect response models which also exhibit recession profiles with slight sigmoidity and a single terminal inflection point at higher doses. The drug concentration at inflection Cfp is < or = IC50 or SC50 (drug concentrations causing half-maximal inhibition or stimulation), while the inflection response (Rfp) attains constant values at larger doses. Indirect Response Models I, III, and IV have nearly linear return slopes for a wide range of doses which are governed by the disposition slope lambda z of the drug, loss constant kout of the response, maximum inhibition (Imax) or stimulation (Smax) factors, and a unique fractional constant (0 < G < or = 1). Model II exhibits more complex behavior with recession slopes which are less likely to be parallel for various doses. Most indirect responses are expected to show nearly linear recession slopes which are parallel for moderate to large doses and mainly governed by an identical combination of pharmacokinetic (lambda z), system (kout), and dynamic capacity factors (Imax or Smax).
机译：已知随着时间的流逝，直接的药理作用会随着线性的斜率而逐渐减小（Levy's k.m product，J. Pharm。Sci。53：342，1964），间接反应具有相似的行为。用单指数药物布置，对希尔函数的药效学斜率特性进行数学检查，并针对其他药代动力学函数进行了模拟。当药物浓度超过EC50（该浓度引起最大作用的一半，即Emax）时，这两种药效学特征均表现出一个单一的最终拐点（fp）。对于直接效应，发现Cfp（fp处的药物浓度）= EC50，确定了拐点时间的决定因素，并且Slopefp = -lambda z gamma Emax / 4，其中lambda z是末端处置斜率，gamma是希尔系数。在四个基本的间接响应模型中探讨了这些特征，这些模型还显示出具有轻微的乙状结肠和较高剂量下的单个最终拐点的衰退曲线。拐点Cfp处的药物浓度小于或等于IC50或SC50（引起最大抑制或刺激一半的药物浓度），而拐点响应（Rfp）在较大剂量下达到恒定值。间接响应模型I，III和IV在各种剂量下具有近乎线性的返回斜率，这取决于药物的配置斜率λz，响应的损失常数kout，最大抑制（Imax）或刺激（Smax）因子和唯一的分数常数（0

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