Ruark Christopher D, Hack C Eric, Robinson Peter J, Mahle Deirdre A, Gearhart Jeffery M
HJF, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton, Ohio 45433; Department of Biomedical Sciences, Wright State University, Dayton, Ohio 45435.
HJF, Molecular Bioeffects Branch, Bioeffects Division, Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton, Ohio 45433.
J Pharm Sci. 2014 Jul;103(7):2189-2198. doi: 10.1002/jps.24011. Epub 2014 May 15.
A mechanistic tissue composition model incorporating passive and active transport for the prediction of steady-state tissue:plasma partition coefficients (K(t:pl)) of chemicals in multiple mammalian species was used to assess interindividual and interspecies variability. This approach predicts K(t:pl) using chemical lipophilicity, pKa, phospholipid membrane binding, and the unbound plasma fraction, together with tissue fractions of water, neutral lipids, neutral and acidic phospholipids, proteins, and pH. Active transport K(t:pl) is predicted using Michaelis-Menten transport parameters. Species-specific biological properties were identified from 126 peer reviewed journal articles, listed in the Supporting Information, for mouse, rat, guinea pig, rabbit, beagle dog, pig, monkey, and human species. Means and coefficients of variation for biological properties were used in a Monte Carlo analysis to assess variability. The results show K(t:pl) interspecies variability for the brain, fat, heart, kidney, liver, lung, muscle, red blood cell, skin, and spleen, but uncertainty in the estimates obscured some differences. Compounds undergoing active transport are shown to have concentration-dependent K(t:pl). This tissue composition-based mechanistic model can be used to predict K(t:pl) for organic chemicals across eight species and 10 tissues, and can be an important component in drug development when scaling K(t:pl) from animal models to humans.
一种结合被动和主动转运的机械组织组成模型，用于预测多种哺乳动物物种中化学物质的稳态组织：血浆分配系数（K(t:pl)），以评估个体间和物种间的变异性。该方法利用化学物质的亲脂性、pKa、磷脂膜结合、未结合血浆分数，以及水、中性脂质、中性和酸性磷脂、蛋白质和pH的组织分数来预测K(t:pl)。利用米氏转运参数预测主动转运的K(t:pl)。从126篇同行评审的期刊文章中确定了小鼠、大鼠、豚鼠、兔子、比格犬、猪、猴子和人类物种的物种特异性生物学特性，这些文章列于支持信息中。生物学特性的均值和变异系数用于蒙特卡罗分析以评估变异性。结果显示大脑、脂肪、心脏、肾脏、肝脏、肺、肌肉、红细胞、皮肤和脾脏的K(t:pl)存在物种间变异性，但估计值的不确定性掩盖了一些差异。显示进行主动转运的化合物具有浓度依赖性的K(t:pl)。这种基于组织组成的机械模型可用于预测八种物种和十种组织中有机化学物质的K(t:pl)，并且在将K(t:pl)从动物模型扩展到人类时，可为药物开发提供重要组成部分。
