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Abstract

As part of an overall program to develop a framework for evaluating the contribution of structural and physicochemical properties to pharmacokinetics, the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) was examined after i.v. bolus administration in rats. The barbituric acids studied form a true homologous series; therefore any differences in pharmacokinetics, noted between congeners, can be directly linked to the increase in lipophilicity, resulting from the addition of a methylene group. A whole-body physiologically based pharmacokinetic model has been developed, assuming most of the tissues to be well-stirred compartments. Brain and testes, in which distribution for the lower homologues was permeability rate-limited, were represented by two compartments. For each homologue, the model parameters have been optimized, using the tissue concentration-time data. The initial distribution processes in the system were very rapid, making it quite stiff, and essentially over before the first samples were taken. A progressively increasing redistribution from lean tissues into adipose on ascending the homologous series was observed, characterized by a tendency for a progressive decrease in the magnitude of the concentration-time profiles for some of the lean and well-perfused tissues, an increase in the adipose concentration-time profile, and an increase in the time to reach the maximum adipose concentration. A shift from permeability rate limitation to perfusion rate limitation of the distribution processes for brain and testes, as well as an increase in the intrinsic hepatic clearance and decrease in the renal clearance with the increase of lipophilicity of the homologues, were quantified. An increase in the total unbound volume of distribution on ascending the homologous series was also observed. Muscle was found to be the major drug depot at steady state, accounting for approximately 50% of the total unbound volume of distribution, regardless of the lipophilicity of the homologue; the unbound volume of distribution of adipose increases more than 10-fold with the increase of lipophilicity.

The Nature of the Dietary Protein Impacts the Tissue-to-Diet 15N Discrimination Factors in Laboratory Rats

“…The rats were anesthetized with an intraperitoneal injection of sodium pentobarbital (100 mg/kg of BW, a dose which is too small to significantly affect the measured isotopic signatures based on the mode of administration of this anesthetic and on distribution kinetics of barbiturates in tissues and plasma of rats [49]). The abdomen was opened and approximately 5 ml of blood were quickly withdrawn from the vena cava.…”

Development and Application of Physiologically Based Pharmacokinetic-Modeling Tools to Support Drug Discovery

“…The assumption of perfusion-limitation may be justified for rapidly permeating compounds in highly perfused tissues like heart, liver, or kidney. However, larger tissues such as muscle and skin, slowly perfused tissues like adipose tissue, tissues with a permeability barrier such as brain and testes, or compounds that permeate slowly across cell membranes cause deviations from the well-stirred model [10]. This permeability limitation is found with many compounds and is indicated by a longer distribution phase in the concentration ± time profile [11].…”

“…A more advanced model of drug distribution within an organ can be derived by assuming more than one tissue compartment. For instance, a more sophisticated reflection of the tissue anatomy can be obtained by separating the tissue into two compartments reflecting vascular space and the remaining tissue [10], or even three compartments further dividing the remaining tissue into interstitial space and intracellular space [11]. However, the subdivision into several tissue compartments requires additional physiological data on the size of these compartments as well as mechanistic information on the compound transfer between them.…”

“…This can, however, be achieved by replacing the initial input data from higher throughput in vitro ADME assays with higher quality input parameters deriving from more sophisticated PK studies [10]. These are performed later in the process for selected compounds to obtain a more profound PK characterization thereby aiding the selection of development candidates.…”

Drug structure–transport relationships

“…They studied the distribution kinetics of nine 5-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) after i.v. bolus administration in rats using well-stirred organ compartments and assuming that either permeability rate limitation or perfusion rate limitation may be involved in the distribution processes [148]. Muscle accounted for ~ 50% of the total unbound volume of distribution for all compounds.…”