Pelekis M, Poulin P, Krishnan K
Département de médecine du travail et d'hygiène du milieu, Faculté de médecine, Université de Montréal, Canada.
Toxicol Ind Health. 1995 Sep-Oct;11(5):511-22. doi: 10.1177/074823379501100505.
The objective of this study was to develop an approach for incorporating tissue composition data into physiologically based pharmacokinetic (PBPK) models in order to facilitate "built-in" calculation of tissue: air partition coefficients (PCs) of volatile organic chemicals. The approach involved characterizing tissue compartments within PBPK models as a mixture of neutral lipids, phospholipids, and water (instead of using the conventional description of them as "empty" boxes). This approach enabled automated calculation of the tissue solubility of chemicals from n-octanol and water solubility data, since these data approximate those of solubility in tissue lipids and water. Tissue solubility was divided by the saturable vapor concentration at 37 degrees C to estimate the tissue: air PCs within PBPK models, according to the method of Poulin and Krishnan (1995c). The highest and lowest lipid and water levels for human muscle, liver, and adipose tissues were obtained from the literature and incorporated within the tissue composition-based PBPK model to calculate the tissue: air PCs of dichloromethane (DCM) and simulate the pharmacokinetics of DCM in humans. The PC values predicted for human tissues were comparable to those estimated using rat tissues in cases where the relative levels of lipids and water were comparable in both species. These results suggest that the default assumption of using rat tissue: air PCs in human PBPK models may be acceptable for certain tissues (liver, adipose tissues), but questionable for others (e.g., muscle). The PBPK modeling exercise indicated that the interindividual differences in tissue dose arising from variations of tissue: air PCs may not be reflected sufficiently by venous blood concentrations. Overall, the present approach of incorporating tissue composition data into PBPK models would not only enhance the biological basis of these models but also provide a means of evaluating the impact of interindividual and interspecies differences in tissue composition on the tissue dose surrogates used in PBPK-based risk assessments.
本研究的目的是开发一种方法，将组织成分数据纳入基于生理的药代动力学（PBPK）模型，以便于“内置”计算挥发性有机化合物的组织：空气分配系数（PCs）。该方法涉及将PBPK模型中的组织隔室表征为中性脂质、磷脂和水的混合物（而不是使用传统的将它们描述为“空”盒子）。这种方法能够根据正辛醇和水溶性数据自动计算化学物质在组织中的溶解度，因为这些数据近似于在组织脂质和水中的溶解度。根据Poulin和Krishnan（1995c）的方法，将组织溶解度除以37℃时的饱和蒸汽浓度，以估计PBPK模型中的组织：空气PCs。从文献中获取人体肌肉、肝脏和脂肪组织的最高和最低脂质及水含量，并纳入基于组织成分的PBPK模型，以计算二氯甲烷（DCM）的组织：空气PCs，并模拟DCM在人体中的药代动力学。在两种物种中脂质和水的相对水平相当的情况下，预测的人体组织PC值与使用大鼠组织估计的值相当。这些结果表明，在人体PBPK模型中使用大鼠组织：空气PCs的默认假设对于某些组织（肝脏、脂肪组织）可能是可以接受的，但对于其他组织（例如肌肉）则值得怀疑。PBPK建模练习表明，由组织：空气PCs变化引起的组织剂量个体间差异可能无法通过静脉血浓度充分反映。总体而言，将组织成分数据纳入PBPK模型的当前方法不仅会增强这些模型的生物学基础，还会提供一种手段来评估组织成分个体间和种间差异对基于PBPK的风险评估中使用的组织剂量替代指标的影响。
