Passive Diffusion of Weak Organic Electrolytes across Caco‐2 Cell Monolayers: Uncoupling the Contributions of Hydrodynamic, Transcellular, and Paracellular Barriers

• Published in: Journal of pharmaceutical sciences 1995-10, Vol.84 (10), p.1197-1204
• Main Authors: Adson, Anthony, Burton, Philip S., Raub, Thomas J., Barsuhn, Craig L., Audus, Kenneth L., Ho, Norman F.H.
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacokinetics; Biological and medical sciences; Biological Transport; Caco-2 Cells - metabolism; Carbon Radioisotopes; Cell Membrane Permeability; Chemical Phenomena; Chemistry, Physical; Diffusion; Electrolytes - pharmacokinetics; General pharmacology; Humans; Hydrogen-Ion Concentration; Kinetics; Mathematical Computing; Medical sciences; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Testosterone - pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600841011

A systematic approach was used to demonstrate the quantitative interplay of pH, pKa, lipophilicity, charged and uncharged molecular species, molecular size, aqueous diffusivity, and stirring in passive transport across the aqueous boundary layer, microporous filter support, and transcellular and paracellular barriers in Caco‐2 cell monolayers. The relationship of permeability of the aqueous boundary layer and hydrodynamic stirring was elucidated from transmonolayer fluxes of testosterone. Adrenergic receptor antagonists including propranolol (PPL), alprenolol (APL), pindolol (PDL), and atenolol (ATL) represented the model series of structurally similar weak bases with pKavalues between 8.8 and 9.65. Although intrinsically lipophilic, their apparent log PC (n‐octanol/water) at pH 7.4 and 6.5 ranged from −2.6 to 1.3. Effective permeability coefficients (Pe) correlated with log PC at both pH 7.4 and 6.5 showing a single sigmoidal‐like curve: PPL > APL > PDL ≥ ATL. ThePeapproached a minimum plateau value established by the protonated ATL for the paracellular route (pore radius of 12 Å) by molecular size‐restricted diffusion within a negative electrostatic field of force. ThePeof the weak bases was delineated into component permeability coefficients of the aqueous boundary layer and porous filter support, the intrinsic permeabilities of charged and uncharged species for the transcellular and paracellular routes, and the extent to which the routes were utilized at each pH. This study emphasized a generally applicable approach to quantitatively analyze passive transport data on weak organic electrolytes and neutral molecules generated using cell culture monolayers.