Levitt David G
Department of Integrative Biology and Physiology, University of Minnesota, 6-125 Jackson Hall, 321 Church St. S E, Minneapolis, MN 55455, USA.
BMC Clin Pharmacol. 2010 Jan 7;10:1. doi: 10.1186/1472-6904-10-1.
The goal of physiologically based pharmacokinetics (PBPK) is to predict drug kinetics from an understanding of the organ/blood exchange. The standard approach is to assume that the organ is "flow limited" which means that the venous blood leaving the organ equilibrates with the well-stirred tissue compartment. Although this assumption is valid for most solutes, it has been shown to be incorrect for several very highly fat soluble compounds which appear to be "diffusion limited". This paper describes the physical basis of this adipose diffusion limitation and its quantitative dependence on the blood/water (Kbld-wat) and octanol/water (Kow) partition coefficient.
Experimental measurements of the time dependent rat blood and adipose concentration following either intravenous or oral input were used to estimate the "apparent" adipose perfusion rate (FA) assuming that the tissue is flow limited. It is shown that the ratio of FA to the anatomic perfusion rate (F) provides a measure of the diffusion limitation. A quantitative relationship between this diffusion limitation and Kbld-wat and Kow is derived. This analysis was applied to previously published data, including the Oberg et. al. measurements of the rat plasma and adipose tissue concentration following an oral dose of a mixture of 13 different polychlorinated biphenyls.
Solutes become diffusion limited at values of log Kow greater than about 5.6, with the adipose-blood exchange rate reduced by a factor of about 30 for a solute with a log Kow of 7.36. Quantitatively, a plot of FA/F versus Kow is well described assuming an adipose permeability-surface area product (PS) of 750/min. This PS corresponds to a 0.14 micron aqueous layer separating the well-stirred blood from the adipose lipid. This is approximately equal to the thickness of the rat adipose capillary endothelium.
These results can be used to quantitate the adipose-blood diffusion limitation as a function of Kow. This is especially important for the highly fat soluble persistent organic chemicals (e.g. polychlorinated biphenyls, dioxins) whose pharmacokinetics are primarily determined by the adipose-blood exchange kinetics.
基于生理的药代动力学（PBPK）的目标是通过理解器官/血液交换来预测药物动力学。标准方法是假设器官是“血流限制型”，这意味着离开器官的静脉血与充分搅拌的组织隔室达到平衡。尽管这个假设对大多数溶质是有效的，但已表明对于几种非常高脂溶性的化合物是不正确的，这些化合物似乎是“扩散限制型”。本文描述了这种脂肪扩散限制的物理基础及其对血液/水（Kbld-wat）和正辛醇/水（Kow）分配系数的定量依赖性。
在假设组织为血流限制型的情况下，通过对静脉注射或口服给药后大鼠血液和脂肪浓度随时间变化的实验测量来估计“表观”脂肪灌注率（FA）。结果表明，FA与解剖灌注率（F）的比值提供了扩散限制的一种度量。推导了这种扩散限制与Kbld-wat和Kow之间的定量关系。该分析应用于先前发表的数据，包括奥伯格等人对口服13种不同多氯联苯混合物后大鼠血浆和脂肪组织浓度的测量。
当log Kow大于约5.6时，溶质变为扩散限制型，对于log Kow为7.36的溶质，脂肪-血液交换率降低约30倍。定量地说，假设脂肪通透表面积乘积（PS）为750/分钟，则FA/F与Kow的关系图能得到很好的描述。这个PS对应于一层0.14微米厚的水层，将充分搅拌的血液与脂肪脂质分隔开。这大约等于大鼠脂肪毛细血管内皮的厚度。
这些结果可用于定量脂肪-血液扩散限制作为Kow的函数。这对于高脂溶性持久性有机化学物质（如多氯联苯、二恶英）尤为重要，其药代动力学主要由脂肪-血液交换动力学决定。
