Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions

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ABSTRACT:

A key component of whole body physiologically based pharmacokinetic (WBPBPK) models is the tissue-to-plasma water partition coefficients (Kpu's). The predictability of Kpu values using mechanistically derived equations has been investigated for 7 very weak bases, 20 acids, 4 neutral drugs and 8 zwitterions in rat adipose, bone, brain, gut, heart, kidney, liver, lung, muscle, pancreas, skin, spleen and thymus. These equations incorporate expressions for dissolution in tissue water and, partitioning into neutral lipids and neutral phospholipids. Additionally, associations with acidic phospholipids were incorporated for zwitterions with a highly basic functionality, or extracellular proteins for the other compound classes. The affinity for these cellular constituents was determined from blood cell data or plasma protein binding, respectively. These equations assume drugs are passively distributed and that processes are nonsaturating. Resultant Kpu predictions were more accurate when compared to published equations, with 84% as opposed to 61% of the predicted values agreeing with experimental values to within a factor of 3. This improvement was largely due to the incorporation of distribution processes related to drug ionisation, an issue that is not addressed in earlier equations. Such advancements in parameter prediction will assist WBPBPK modelling, where time, cost and labour requirements greatly deter its application. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association

Section snippets

INTRODUCTION

With the advent of high throughput procedures, medicinal chemists and biologists can rapidly screen novel chemical entities for favourable properties. One important set of properties concerns pharmacokinetic characteristics, which still require considerable effort and resource for assessment. While in vitro data can be used to gain a measure of intestinal permeability and hepatic metabolic stability, the issue of assessing likely tissue distribution remains problematic. Consequently the current

Underlying Considerations

In a previous study,7 a mechanistic equation for predicting Kpu values of moderate-to-strong bases was developed from the knowledge that these drugs preferentially interact with tissue acidic phospholipids (phosphatidylserine, phosphatidylglycerol (mono and di), phosphatidylinositol and phosphatidic acid) through electrostatic interactions. Such interactions are restricted to bases that are significantly ionised at physiological pH so will not apply to weaker bases and other drug classes.

New Equations (Equations 10 and 14)

Overall, the accuracy of the Kpu predictions for 7 very weak bases, 20 acids, 4 neutral drugs, 2 group 2 zwitterions and 6 group 1 zwitterions in 13 rat tissues (n = 370 observations in total) was good, with mean predicted-to-experimental Kpu ratios of 0.91–1.62 for the different drug classes thereby indicating no significant bias in the mechanistic predictions. Additionally, little difference was generally observed between Kpu values predicted using experimental compared to predicted LogP

DISCUSSION

Many of the issues discussed in a preceding publication7 are relevant to this research and have been briefly summarised here, along with areas of interest relating to the compounds detailed in this study. However, the reader is still encouraged to peruse this earlier publication.

One issue generic to both this and the preceding publication7 is variability and uncertainty inherent to the biological system and parameter determinations. These variables are not currently accommodated in mechanistic

Acknowledgements

Financial support for this project was provided by the following Centre for Applied Pharmacokinetic Research (The University of Manchester) Consortium members, GlaxoSmithKline, Novartis, Pfizer, Servier and Eli Lilly.

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