A new nonlinear equation for the tissue/blood partition coefficients of neutral compounds.

A nonlinear model equation based on tissue composition (a content of lipids, proteins, and water) for the tissue/blood partition coefficients of compounds was developed. Based on this model, our nonlinear regression analysis for neutral compounds partitioning into the kidney, brain, muscle, lung, liver, heart, and fat resulted in equations with high fitting power (training set: n = 166, r(2) = 0.851, s = 0.260, Q(2) = 0.833) and strong predictive power (test set: n = 49, r(2) = 0.851, s = 0.246, Q(2) = 0.836). This model shows that the tissue/blood partition coefficients of a compound depend strongly on tissue compositions. The magnitudes of partition coefficients of a compound in different tissues are mainly modulated by volume fractions or weight fractions of tissue compositions.

[1]  Harpreet S. Chadha,et al.  Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain. , 1994, Journal of pharmaceutical sciences.

[2]  Lemont B. Kier,et al.  Modeling Blood-Brain Barrier Partitioning Using the Electrotopological State , 2002, J. Chem. Inf. Comput. Sci..

[3]  Huabei Zhang,et al.  pH‐Dependent Partitioning of Acidic and Basic Drugs into Liposomes—A Quantitative Structure‐Activity Relationship Analysis , 2001 .

[4]  N. Bodor,et al.  A new method for the estimation of the aqueous solubility of organic compounds. , 1992, Journal of pharmaceutical sciences.

[5]  A. J. Hopfinger,et al.  Predicting Blood–Brain Barrier Partitioning of Organic Molecules Using Membrane–Interaction QSAR Analysis , 2002, Pharmaceutical Research.

[6]  Kenneth J. Miller,et al.  Additivity methods in molecular polarizability , 1990 .

[7]  R. M. Muir,et al.  Correlation of Biological Activity of Phenoxyacetic Acids with Hammett Substituent Constants and Partition Coefficients , 1962, Nature.

[8]  F. Lombardo,et al.  Computation of brain-blood partitioning of organic solutes via free energy calculations. , 1996, Journal of medicinal chemistry.

[9]  F. Theil,et al.  Prediction of adipose tissue: plasma partition coefficients for structurally unrelated drugs. , 2001, Journal of pharmaceutical sciences.

[10]  S. Björkman.  Prediction of the volume of distribution of a drug: which tissue‐plasma partition coefficients are needed? , 2002, The Journal of pharmacy and pharmacology.

[11]  Patrick Poulin,et al.  Prediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition. , 2002, Journal of pharmaceutical sciences.

[12]  J. DeJongh,et al.  A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans , 1997, Archives of Toxicology.

[13]  O. A. Raevsky.  QUANTIFICATION OF NON-COVALENT INTERACTIONS ON THE BASIS OF THE THERMODYNAMIC HYDROGEN BOND PARAMETERS , 1997 .

[14]  Viera Lukacova,et al.  A Model‐based Dependence of the Human Tissue/Blood Partition Coefficients of Chemicals on Lipophilicity and Tissue Composition , 1999 .

[15]  Michael H. Abraham,et al.  A general treatment of hydrogen bond complexation constants in tetrachloromethane , 1988 .

[16]  N. Zefirov,et al.  Approximate molecular electrostatic potential computations: applications to quantitative structure-activity relationships , 1994 .