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

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...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2006-06, Vol.95 (6), p.1238-1257
Main Authors: Rodgers, Trudy, Rowland, Malcolm
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood Proteins - metabolism
Body Fluid Compartments
Computer Simulation
Erythrocytes - metabolism
General pharmacology
in silico modelling
Medical sciences
Models, Biological
Octanols - chemistry
partition coefficients
PBPK modelling
Pharmaceutical technology. Pharmaceutical industry
Pharmacokinetics
Pharmacology. Drug treatments
phospholipids
Phospholipids - chemistry
physicochemical properties
physiological model
Predictive Value of Tests
QSAR
Quantitative Structure-Activity Relationship
Rats
Tissue Distribution
tissue partition
Water - chemistry
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Summary: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
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.20502