Pharmacokinetics, Pharmacodynamics and Drug MetabolismOn the Accuracy of Determination of Unbound Drug Fraction in Tissue using Diluted Tissue Homogenate
Section snippets
INTRODUCTION
Distribution of drug in tissues is one of the features that determine its concentration profile and pharmacological activity. At steady state, it can be characterized by the value of unbound drug fraction in each tissue, fut, which is defined as
where Cut is the concentration of unbound drug in tissue extracellular water and Ct is the total tissue concentration. At equilibrium, the unbound drug concentration in plasma, Cup, is equal to Cut because the pH of plasma and tissue
RESULTS
To derive the equation for fut, we need to consider the equilibrium drug distribution between tissue compartments, which are the extra- and intracellular water, and membrane and connective tissues (considered as a single compartment).1,2 Tissue extracellular water has pH 7.4, while intracellular water has pH 7.0. At equilibrium, the concentrations of unbound neutral drug in extracellular water, , is the same as unbound neutral drug concentration in intracellular water, , so that
DISCUSSION
A possible underestimation of fut for acidic compounds and overestimation for basic ones occurs because of pH difference between extra- and intracellular water. Acidic compounds tend to stay in the extracellular water, whereas the basic compounds distribute more into intracellular water (due to its lower pH). This selective distribution of compounds does not exist in tissue homogenate, so that the measured fut,h may not adequately provide the value of fut when a simplified calculation (Eq. 4)
APPENDIX 1
Tissue homogenate can be considered as comprised of water at pH 7.4 and membrane–connective tissue constituent. The water of homogenate includes both the extra- and intracellular water from tissue and the added water for dilution. Thus, its volume, VW*, is equal to
It is assumed here that the tissue was perfused with water to remove blood and consequently to eliminate a possible error in measurement of fut,h because of the distribution of compound into residual blood. Protein
List of Notations
AUCp, AUCt—the areas under the drug concentration-time curves for plasma and tissue, respectively;
Cp—total drug plasma concentration;
Ct—total tissue concentration;
Ct,h—total drug concentration in tissue homogenate;
Cut,h—unbound drug concentration in tissue homogenate;
Cut—concentration of unbound drug in tissue extracellular water;
CEW, CIW—the total drug concentrations in extra- and intracellular water, respectively;
,—the concentrations of unbound neutral drug in tissue extra- and
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2020, Trends in Pharmacological SciencesCitation Excerpt :Given the dependency on physicochemical properties, Vd is not a parameter that is readily adaptable in a given chemical series; rather, boundary estimates of Vd, and specifying a desired human elimination half-life (t1/2) can help identify a target CL value to optimize against. Vd is reasonably predictable from physicochemical properties, in silico [34,35] and in vitro methods [36,37]. Using preclinical in vivo PK data and correcting for species plasma protein binding (PPB) differences, Vd is the most predictable of PK parameters; if unbound volume of distribution (Vu) is consistent across species (it is typically conserved within twofold), human Vd can be predicted from animal data by estimating Vu [6,14,31,38].
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2017, Comprehensive Medicinal Chemistry IIIExploration of PBPK Model—Calculation of Drug Time Course in Tissue Using IV Bolus Drug Plasma Concentration-Time Profile and the Physiological Parameters of the Organ
2016, Journal of Pharmaceutical SciencesCitation Excerpt :The PT-p is then calculated as PT-p = fup/fuT. This method may provide PT-p rather accurately for neutral compounds but possibly overestimate PT-p more than 4-fold for basic compounds and underestimate Pt-p more than 2-fold for acidic compounds.10 In general, this occurs due to pH difference between tissue extracellular water (pH 7.4) and tissue intracellular water (pH 7.0).
An algorithm for evaluating potential tissue drug distribution in toxicology studies from readily available pharmacokinetic parameters
2013, Journal of Pharmaceutical SciencesCitation Excerpt :The substrate concentration used in the in vitro experiments to estimate fup varied from 5 to 50 μM, which covers the low and high plasma drug concentration observed in vivo in rats for these drugs. The value of fup was determined by using a previously described equilibrium dialysis method.19 In the presence of relevant transporter effects in one or several tissues, the use of fup value in the above Eq.4 would be limited.20-22
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