The Role of Permeability in Drug ADME/PK, Interactions and Toxicity—Presentation of a Permeability-Based Classification System (PCS) for Prediction of ADME/PK in Humans

Purpose The objective was to establish in vitro passive permeability ( P e ) vs in vivo fraction absorbed ( f a )-relationships for each passage through the human intestine, liver, renal tubuli and brain, and develop a P e -based ADME/PK classification system (PCS). Materials and Methods P e - and intestinal f a -data were taken from an available data set. Hepatic f a was calculated based on extraction ratios of the unbound fraction of drugs (with support from animal in vivo uptake data). Renal f a (reabsorption) was estimated using renal pharmacokinetic data, and brain f a was predicted using animal in vitro and in vivo brain P e -data. Hepatic and intestinal f a -data were used to predict bile excretion potential. Results Relationships were established, including predicted curves for bile excretion potential and minimum oral bioavailability, and a 4-Class PCS was developed: I (very high P e ; elimination mainly by metabolism); II (high P e ) and III (intermediate P e and incomplete f a ); IV (low P e and f a ). The system enables assessment of potential drug–drug transport interactions, and drug and metabolite organ trapping . Conclusions The PCS and high quality P e -data (with and without active transport) are believed to be useful for predictions and understanding of ADME/PK, elimination routes, and potential interactions and organ trapping /toxicity in humans.