TOXICOKINETICS Joost DeJongh á Henk J.M. Verhaar Joop L.M. Hermens A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coef®cients of organic chemicals in rats and humans Received: 6 March 1997 / Accepted: 18 August 1997 Abstract The present study describes quantitative property-property relationships (QPPRs) for the parti- tioning of organic chemicals between blood and tissue homogenates from both rats and humans. The n-octa- nol/water partition coecient (K ow ) is used as a non- biological descriptor. QPPRs for human tissue-blood partition coecients (PCs) were derived from a dataset of 24 volatile organic compounds in blood, liver, muscle, fat, kidney and brain tissue homogenates. QPPRs were also derived for the PCs of rat tissues, using a dataset of 42 volatile organic compounds in blood, liver, muscle and fat tissue homogenates. These QPPRs were evalu- ated using a test set of 10 compounds for human tissues and a test set of 14 compounds for rat tissues. For both human and rat test sets, it was generally observed that most estimated PCs were within a range of 50±200% of their experimental values. The present approach is concluded to oer a rapid means for the estimation of tissue-blood PCs of compounds on the basis of K ow values. In addition, indications for a possible role of tissue components other than lipid and water in the tissue-blood partitioning process of compounds were observed from the calibration results of the model. Key words Partition coecients á Physiologically based- pharmacokinetics (PB-PK) á Distribution á Modelling Introduction The application of physiologically based-pharmacoki- netic (PB-PK) models for studying the role of kinetics in the toxicity of xenobiotics to animals has substantially increased during the last decade (Andersen 1991; Leung 1991; Droz 1993; Filser et al. 1995). In contrast to the `classical', data based kinetic models, PB-PK models have a biologically based model structure and feature a clear distinction between physiological and compound-speci®c model parameters (Yang and Andersen 1994). Thus, PB- PK models oer the advantage of a priori estimation of kinetic behaviour on the basis of independently derived parameters for the physiology of the animal and the in- teraction of the chemical with the tissues. Compound speci®c PB-PK model parameters, such as tissue-blood and blood-air partition coecients and bio- transformation rates, can be obtained by adjusting the parameters to data derived from in vivo studies or by direct measurement of parameters in vitro (Kedderis et al. 1993; Johanson 1993; DeJongh and Blaauboer 1996). Alterna- tively, some attempts have been made to predict biological partition coecients from water and or/air solubility (Paterson and Mackay 1989; Poulin and Krishnan 1996a, b) or to establish empirical QPPRs between partition co- ecients and non-biological properties (Sato and Naka- jima 1979; Fiserova-Bergerova and Diaz 1986; Gargas et al. 1988; Csanady and Laib 1990; Connel et al. 1993). The present study describes the distribution of com- pounds between body tissues as a function of water and lipid content of tissues and the n-octanol/water partition coecient (K ow ). K ow has been shown to be a good model parameter for lipid-water partitioning in numer- ous studies (Seydel and Schaper 1982; Hansch et al. 1989). In addition, fairly accurate calculations of the K ow values for organic compounds can be made on the basis of chemical structure (Chou and Jurs 1980; Meylan and Howard 1995). This study was undertaken to es- tablish a semi-mechanistic algorithm for rapid estima- tion of tissue-blood partition coecients of xenobiotics from their partitioning in the octanol-water system. Methods Model structure A general model for the partitioning of compounds between tissues and blood is established based on the following assumptions. Arch Toxicol (1997) 72: 17±25 Ó Springer-Verlag 1997 J. DeJongh (&) á H.J.M. Verhaar á J.L.M. Hermens Research Institute of Toxicology (RITOX), P.O. Box 80.176, 3508 TD Utrecht, The Netherlands