Abstract
BackgroundThe 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.MethodsExperimental 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.ResultsSolutes 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.ConclusionsThese 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.
Highlights
The goal of physiologically based pharmacokinetics (PBPK) is to predict drug kinetics from an understanding of the organ/blood exchange
Because of the large qualitative difference in the kinetics for the 3 solutes shown in Figure 2, there is no question that there are significant differences in the corresponding values of FA
The capillary permeability limitation produced by this blood lipid solute binding is directly analogous to the carbon monoxide (CO) pulmonary diffusion limitation that results from the high affinity of hemoglobin for CO [24]
Summary
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. 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”. The most basic approach (and the standard one) is to assume that this exchange is “flow limited” - that is, the venous blood leaving the capillary has equilibrated with the well mixed tissue space. These solutes represent relatively rare exceptions and the great majority of solutes that are used in PBPK modeling are highly lipid soluble with high (nearly infinite) cell membrane permeability and the predictions of the flow limited PBPK model generally provides good agreement with the experimental pharmacokinetics
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