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 (K(p)) and resulting volume of distribution at steady state (V(ss)) are substantially overpredicted for several highly lipophilic drugs. This effect was observed particularly with the published version of the tissue-composition-based model, which used experimentally determined unbound fraction in plasma (fu(p)) as input for drugs. The reasons for the unreasonably high V(ss) predictions were investigated in this study for 14 highly lipophilic compounds with a log n-octanol-water partition coefficient (log P(ow)) of at least 5.8. Here, we argue that the experimentally determined fu(p) is inaccurate for these compounds, which affected the prediction of K(p) and V(ss). Alternatively, the tissue-plasma ratio of neutral lipids (nl) equivalent was used as the main factor governing K(p), and hence V(ss), in addition to log P(ow). The average fold error of deviation between the predicted and observed human V(ss) 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 V(ss) into physiologically based pharmacokinetic (PBPK) models.