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J Pharm Sci. 2000 Jan;89(1):16-35.

A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery.

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1
Department of Drug Metabolism & Pharmacokinetics, F. Hoffmann-La Roche, Ltd., Pharma Research, CH-4070 Basel, Switzerland. patrick.poulin@roche.com

Abstract

The tissue:plasma (P(t:p)) partition coefficients (PCs) are important drug-specific input parameters in physiologically based pharmacokinetic (PBPK) models used to estimate the disposition of drugs in biota. Until now the use of PBPK models in early stages of the drug discovery process was not possible, since the estimation of P(t:p) of new drug candidates by using conventional in vitro and/or in vivo methods is too time and cost intensive. The objectives of the study were (i) to develop and validate two mechanistic equations for predicting a priori the rabbit, rat and mouse P(t:p) of non-adipose and non-excretory tissues (bone, brain, heart, intestine, lung, muscle, skin, spleen) for 65 structurally unrelated drugs and (ii) to evaluate the adequacy of using P(t:p) of muscle as predictors for P(t:p) of other tissues. The first equation predicts P(t:p) at steady state, assuming a homogenous distribution and passive diffusion of drugs in tissues, from a ratio of solubility and macromolecular binding between tissues and plasma. The ratio of solubility was estimated from log vegetable oil:water PCs (K(vo:w)) of drugs and lipid and water levels in tissues and plasma, whereas the ratio of macromolecular binding for drugs was estimated from tissue interstitial fluid-to-plasma concentration ratios of albumin, globulins and lipoproteins. The second equation predicts P(t:p) of drugs residing predominantly in the interstitial space of tissues. Therefore, the fractional volume content of interstitial space in each tissue replaced drug solubilities in the first equation. Following the development of these equations, regression analyses between P(t:p) of muscle and those of the other tissues were examined. The average ratio of predicted-to-experimental P(t:p) values was 1.26 (SD = 1.40, r = 0.90, n = 269), and 85% of the 269 predicted values were within a factor of three of the corresponding literature values obtained under in vivo and in vitro conditions. For predicted and experimental P(t:p), linear relationships (r > 0.9 in most cases) were observed between muscle and other tissues, suggesting that P(t:p) of muscle is a good predictor for the P(t:p) of other tissues. The two previous equations could explain the mechanistic basis of these linear relationships. The practical aim of this study is a worthwhile goal for pharmacokinetic screening of new drug candidates.

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