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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Quantitative structure-pharmacokinetics relationships: II. A mechanistically based model to evaluate the relationship between tissue distribution parameters and compound lipophilicity.
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Quantitative structure-pharmacokinetics relationships: II. A mechanistically based model to evaluate the relationship between tissue distribution parameters and compound lipophilicity.

机译：定量结构与药代动力学的关系：II。基于机械的模型，用于评估组织分布参数与复合亲脂性之间的关系。

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摘要

The tissue-to-unbound plasma distribution coefficients (Kpus) of 14 rat tissues after i.v. administration of nine 5-n-alkyl-5-ethyl barbituric acids, determined in a previous study, were used to identify a model of the relationship between tissue distribution and lipophilicity of the homologs, expressed in terms of their octanol to water partition ratio, P. Based on mechanistic considerations and assumptions, the parameter model was expressed as Kpu tau = fw.tau [1 + a tau (nPt.tau)Pb tau], where fw.tau is the tissue water content. (nPt. tau) is the binding capacity of the tissue, n is the number of the binding sites, a tau and b tau are the parameters of the relationship Ka tau = a tau Pb tau; and Ka tau is the binding association constant of each tissue. The parameter model was linearized and fitted to the predetermined Kpu values, yielding correlation coefficients ranging between .940 and .997. The predictive performance of the parameter model was evaluated using a leave-one-out procedure with subsequent computation of the mean prediction error (ME = measurement of the prediction bias) and the square root of the mean squared prediction error (RMSE = measurement of the prediction accuracy). The ME varied between -22.48 and 61.14%, indicating a slight tendency for overpredicting. The RMSE was between 24.73 and 102% for the individual tissues across the different homologs; and between 28.33 and 85.2% for the individual homologs across the different tissues. The apparently high Kpu prediction errors, when translated through the low sensitivity of the barbiturate whole-body physiologically based pharmacokinetic model, established previously, leads to predicted tissue concentration-time profiles within 5 to 20% of the original ones. Therefore, it is concluded, that the identified mechanistically based model is a good predictor of the tissue-to-unbound Kpus in the rat tissues.
机译：静脉注射后14个大鼠组织的组织间未结合血浆分布系数（Kpus）。通过先前研究确定的9种5-n-烷基-5-乙基巴比妥酸的施用，可以确定组织分布与同系物亲脂性之间关系的模型，以辛醇与水的分配比表示， P.基于机理考虑和假设，参数模型表示为Kpu tau = fw.tau [1 + a tau（nPt.tau）Pb tau]，其中fw.tau是组织含水量。 （nPt.tau）是组织的结合能力，n是结合位点的数目，tau和btau是关系的参数Ka tau = a tau Pb tau; Ka tau是每个组织的结合缔合常数。参数模型被线性化并拟合到预定的Kpu值，产生的相关系数在.940和.997之间。使用留一法程序评估参数模型的预测性能，随后计算均值预测误差（ME =预测偏差的度量）和均方根预测误差的平方根（RMSE =均方根的度量）预测准确性）。 ME在-22.48％和61.14％之间变化，表明略有过度预测的趋势。跨不同同源物的单个组织的RMSE在24.73至102％之间。在不同组织中的单个同源物在28.33％至85.2％之间。当通过先前建立的巴比妥酸盐全身基于生理学的药代动力学模型的低敏感性进行翻译时，明显较高的Kpu预测误差会导致预测的组织浓度-时间曲线在原始曲线的5％到20％之内。因此，得出的结论是，所确定的基于机械的模型是大鼠组织中组织到未结合的Kpus的良好预测指标。

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