PT - JOURNAL ARTICLE AU - Maximilian V. Schmitt AU - Andreas Reichel AU - Xiaohui Liu AU - Gert Fricker AU - Philip Lienau TI - Extension of the mechanistic tissue distribution model of Rodgers & Rowland by systematic incorporation of lysosomal trapping: impact on Kpu and volume of distribution predictions in the rat AID - 10.1124/dmd.120.000161 DP - 2020 Jan 01 TA - Drug Metabolism and Disposition PG - DMD-AR-2020-000161 4099 - http://dmd.aspetjournals.org/content/early/2020/11/04/dmd.120.000161.short 4100 - http://dmd.aspetjournals.org/content/early/2020/11/04/dmd.120.000161.full AB - Physiologically based pharmacokinetic (PBPK) modelling has become a standard tool to predict drug distribution in early stages of drug discovery which however currently does not encompass lysosomal trapping. For basic-lipophilic compounds lysosomal sequestration is known to potentially influence intracellular as well as tissue distribution. The aim of our research was to reliably predict the lysosomal drug content and ultimately integrate this mechanism into PK prediction models. First, we further validated our previously presented method to predict the lysosomal drug content (Schmitt et al., 2019) for a larger set of compounds (n=41) showing a very good predictivity. Using the lysosomal marker lipid bis(monoacylglycero)-phosphate (BMP), we estimated the lysosomal volume fraction for all major tissues in the rat ranging from 0.03% for adipose up to 5.3% for spleen. The pH-driven lysosomal trapping was then estimated and fully integrated into the mechanistic distribution model published by Rodgers et al. (2005). Predictions of Kpu improved for all lysosome rich tissues. For instance Kpu increased for nicotine 4-fold (spleen) and 2-fold (lung and kidney) and for quinidine 1.8-fold (brain). Although for most other drugs the effects were much less ({less than or equal to} 7% ). Overall, the effect was strongest for basic compounds with a lower lipophilicity such as nicotine where the Vuss prediction changed from 1.34 to 1.58 L/kg. For more lipophilic (basic) compounds or those which already show strong interactions with acidic phospholipids the additional contribution of lysosomal trapping was less pronounced. Nevertheless, lysosomal trapping will affect intracellular distribution also of such compounds. Significance Statement The estimation of the lysosomal content in all body tissues facilitated the incorporation of lysosomal sequestration into a general PBPK model leading to improved predictions as well as elucidating its influence on tissue- and subcellular distribution in the rat.