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

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