MOLECULAR STRUCTURE-BASED PREDICTION OF THE PARTITION-COEFFICIENTS OFORGANIC-CHEMICALS FOR PHYSIOLOGICAL PHARMACOKINETIC MODELS

The objectives of the present study were (1) to develop and validate a methodology for predicting tissue:air (P-t:a) and blood:air (P-b:a) p artition coefficients (PCs) of organic chemicals from molecular struct ure information, and (2) to incorporate this methodology within physio logically based pharmacokinetic (PBPK) models to enable automated calc ulation of PCs from molecular structure information provided as input to the model. The proposed methodology involves (1) estimating n-octan ol:water or oil:water (P-o:w) PCs and water:air (P-w:a) PCs at 25 degr ees C of chemicals from their molecular structure information using pr eviously validated fragment constant methods, (2) correcting for the t emperature dependence of vapor pressures using the Clausius-Clapeyron equation to extrapolate the P-w:a to 37 degrees C, and (3) incorporati ng these data along with data on volumes of neutral lipids, phospholip ids, and water in tissues and blood in an algorithm to predict P-t:a a nd P-b:a. The predictions of rat and human P-t:a (liver, muscle, and a dipose tissue) and P-b:a for 17 chemicals obtained with the present me thodology were, in general, within a factor of two of the correspondin g experimental values obtained from the literature. Following the inco rporation of the elements of this methodology within a human PBPK mode l for dichloromethane, the P-t:a and Pb-b:a values were automatically calculated during each run within the model from the molecular structu re information provided as input. The methodological approaches propos ed in this article represent a significant step toward the development of PBPK models from molecular structure information provided as the s ole input.