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首页> 外文期刊>Journal of pharmaceutical sciences. >A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery.
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A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery.

机译：药物的组织：血浆分配系数的先验预测，以利于在药物发现中使用基于生理的药代动力学模型。

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The tissue:plasma (P(t:p)) partition coefficients (PCs) are important drug-specific input parameters in physiologically based pharmacokinetic (PBPK) models used to estimate the disposition of drugs in biota. Until now the use of PBPK models in early stages of the drug discovery process was not possible, since the estimation of P(t:p) of new drug candidates by using conventional in vitro and/or in vivo methods is too time and cost intensive. The objectives of the study were (i) to develop and validate two mechanistic equations for predicting a priori the rabbit, rat and mouse P(t:p) of non-adipose and non-excretory tissues (bone, brain, heart, intestine, lung, muscle, skin, spleen) for 65 structurally unrelated drugs and (ii) to evaluate the adequacy of using P(t:p) of muscle as predictors for P(t:p) of other tissues. The first equation predicts P(t:p) at steady state, assuming a homogenous distribution and passive diffusion of drugs in tissues, from a ratio of solubility and macromolecular binding between tissues and plasma. The ratio of solubility was estimated from log vegetable oil:water PCs (K(vo:w)) of drugs and lipid and water levels in tissues and plasma, whereas the ratio of macromolecular binding for drugs was estimated from tissue interstitial fluid-to-plasma concentration ratios of albumin, globulins and lipoproteins. The second equation predicts P(t:p) of drugs residing predominantly in the interstitial space of tissues. Therefore, the fractional volume content of interstitial space in each tissue replaced drug solubilities in the first equation. Following the development of these equations, regression analyses between P(t:p) of muscle and those of the other tissues were examined. The average ratio of predicted-to-experimental P(t:p) values was 1.26 (SD = 1.40, r = 0.90, n = 269), and 85% of the 269 predicted values were within a factor of three of the corresponding literature values obtained under in vivo and in vitro conditions. For predicted and experimental P(t:p), linear relationships (r > 0.9 in most cases) were observed between muscle and other tissues, suggesting that P(t:p) of muscle is a good predictor for the P(t:p) of other tissues. The two previous equations could explain the mechanistic basis of these linear relationships. The practical aim of this study is a worthwhile goal for pharmacokinetic screening of new drug candidates. Copyright 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:16-35, 2000
机译：组织：血浆（P（t：p））分配系数（PCs）是用于评估生物群中药物配置的基于生理的药代动力学（PBPK）模型中重要的药物特异性输入参数。到目前为止，由于在传统的体外和/或体内方法对新药候选物的P（t：p）进行估算太耗时且成本高昂，因此无法在药物开发过程的早期阶段使用PBPK模型。这项研究的目的是（i）开发和验证两个机制方程，以先验地预测兔，大鼠和小鼠的非脂肪和非排泄组织（骨骼，脑，心脏，肠，肺，肌肉，皮肤，脾脏）中的65种与结构无关的药物，以及（ii）评估使用肌肉的P（t：p）作为其他组织的P（t：p）预测因子的适当性。第一个方程根据组织和血浆之间的溶解度和大分子结合率，假设组织中药物的均匀分布和被动扩散，可以预测稳态下的P（t：p）。溶解度的比率是根据对数植物油：水的PCs（K（vo：w））以及组织和血浆中脂质和水的含量来估算的，而药物的大分子结合率是根据组织间质液与白蛋白，球蛋白和脂蛋白的血浆浓度比。第二个方程式预测主要存在于组织间隙中的药物的P（t：p）。因此，每个组织中间隙空间的体积分数含量取代了第一个方程式中的药物溶解度。随着这些方程式的发展，检查了肌肉与其他组织的P（t：p）之间的回归分析。预测与实验P（t：p）值的平均比率为1.26（SD = 1.40，r = 0.90，n = 269），269个预测值中的85％在相应文献的三倍之内在体内和体外条件下获得的值。对于预测和实验的P（t：p），在肌肉与其他组织之间观察到线性关系（大多数情况下r> 0.9），这表明肌肉的P（t：p）是P（t：p）的良好预测指标）的其他组织。前面的两个方程式可以解释这些线性关系的机理基础。这项研究的实际目标是对新候选药物进行药代动力学筛选的有价值目标。版权所有2000 Wiley-Liss，Inc.和美国药学会J Pharm Sci 89：16-35，2000

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