A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human

Journal Article · Sat Jan 15 00:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.10.014· OSTI ID:21535217

Poulin, Patrick ^[1]; Ekins, Sean ^[2]; Theil, Frank-Peter ^[3]

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1. Quebec City, Quebec (Canada)
2. Collaborations in Chemistry, 601 Runnymede Avenue, Jenkintown, PA 19046 (United States)
3. Genentech, South San Francisco (United States)

A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V{sub ss}) in humans under in vivo conditions. This correlation method demonstrated inaccurate predictions of V{sub ss} for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V{sub ss} of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models.

• OSTI ID: 21535217
• Journal Information: Toxicology and Applied Pharmacology, Vol. 250, Issue 2; Other Information: DOI: 10.1016/j.taap.2010.10.014; PII: S0041-008X(10)00407-2; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANIMALS
BLOOD PLASMA
DRUGS
ERYTHROCYTES
FORECASTING
HUMAN POPULATIONS
HYPOTHESIS
IN VITRO
IN VIVO
PLASMA
SIMULATION
STRUCTURE-ACTIVITY RELATIONSHIPS
TISSUE DISTRIBUTION
TOXICITY
VEGETABLE OILS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
DISTRIBUTION
MATERIALS
OILS
ORGANIC COMPOUNDS
OTHER ORGANIC COMPOUNDS
POPULATIONS