Pharmacokinetics, Pharmacodynamics and Drug Metabolism Advancing Prediction of Tissue Distribution and Volume of Distribution of Highly Lipophilic Compounds from a Simplified Tissue-Composition-Based Model as a Mechanistic Animal Alternative Method

It has been reported that values of tissue–plasma ratios (Kp) and resulting volume of distribution at steady state (Vss) are substantially overpredicted for several highly lipophilic drugs. This effect was observed particularly with the published version of the tissuecomposition-based model, which used experimentally determined unbound fraction in plasma (fup) as input for drugs. The reasons for the unreasonably high Vss predictions were investigated in this study for 14 highly lipophilic compounds with a log n-octanol–water partition coefficient (log Pow) of at least 5.8. Here, we argue that the experimentally determined fup is inaccurate for these compounds, which affected the prediction of Kp and Vss. Alternatively, the tissueplasma ratio of neutral lipids (nl) equivalent was used as the main factor governing Kp, and hence Vss, in addition to log Pow. The average fold error of deviation between the predicted and observed human Vss is 124 for the published model, whereas it significantly decreased to 1.5 for the proposed model. The sensitivity analysis confirmed the importance of nl content and drug lipophilicity. Overall, this study proposes a generic and simplified tissue-composition-based model for highly lipophilic drugs and chemicals, which is a step forward toward improving prediction of Vss into physiologically based pharmacokinetic (PBPK) models. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2250–2261, 2012