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.
OBJECTIVE
The objective was to establish in vitro passive permeability (Pe) vs in vivo fraction absorbed (fa)-relationships for each passage through the human intestine, liver, renal tubuli and brain, and develop a Pe-based ADME/PK classification system (PCS).


METHODS
Pe- and intestinal fa-data were taken from an available data set. Hepatic fa was calculated based on extraction ratios of the unbound fraction of drugs (with support from animal in vivo uptake data). Renal fa (reabsorption) was estimated using renal pharmacokinetic data, and brain fa was predicted using animal in vitro and in vivo brain Pe-data. Hepatic and intestinal fa-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 Pe; elimination mainly by metabolism); II (high Pe) and III (intermediate Pe and incomplete fa); IV (low Pe and fa). The system enables assessment of potential drug-drug transport interactions, and drug and metabolite organ trapping.


CONCLUSIONS
The PCS and high quality Pe-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.
Fagerholm
Urban
U
Clinical Pharmacology, AstraZeneca R&D Södertälje, S-151 85, Södertälje, Sweden. urban.fagerholm@astrazeneca.com
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D003198:Computer Simulation; D004347:Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000145:classification* / Q000378:metabolism*; D010599:Pharmacokinetics; D018570:Risk Assessment; D014116:Toxicology
D004364:Pharmaceutical Preparations
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