The Role of Permeability in Drug ADME/PK, Interactions and Toxicity, and the Permeability‐Based Classification System (PCS)

Permeability (Pe) is one of the key determinants in the absorption, distribution, metabolism, excretion/pharmacokinetics (ADME/PK) of drugs and their metabolites. Predictions of ADME/PK, interactions, elimination routes, exposures, and toxicity require, therefore, that the role of permeability in different organs is considered, investigated and understood. That includes studies of and knowledge about the relation between Pe and fraction absorbed (fa) (or fraction reabsorbed; fra) in various organs, and the interplay between passive permeability and active permeability, metabolism and solubility/dissolution. Relationships between passive Pe and fa in the human intestine, liver, renal tubuli (fra), and brain have been established, and these are the basis of the Permeability-Based Classification System (PCS). This system demonstrates sigmoidal Pe versus fa and fra relationships of different shapes and shifts, and is divided into four permeability categories (very high/high/intermediate/low). Results show or indicate that the liver and brain have comparably high intrinsic passive uptake capacities, metabolism (rather than uptake, diffusion, and dissociation) is the general rate-limiting step in hepatic metabolic clearance (CLH), and few high permeability compounds have dissolution-limited gastrointestinal fa. Active transport processes contribute to the intestinal and hepatic uptake, and renal, biliary, and intestinal drug excretion, of many drugs with limited passive Pe. Active transport could be clinically relevant for brain uptake of both low and high passive permeability compounds. Related drug–drug interactions and polymorphism appear most pronounced for drugs actively absorbed and excreted by the liver. Combined with intrinsic metabolic CL data, the PCS is useful for predictions of CLH, renal and biliary excretion potential, gut-wall extraction ratio, oral bioavailability and effects of polymorphism, and for assessment of potential drug–drug or drug–metabolite interactions, and drug and metabolite organ/cell trapping. Keywords: absorption; classification system; clearance; excretion; interaction; metabolism; permeability; pharmacokinetics; prediction; toxicity