Convective washout reduces the antidiarrheal efficacy of enterocyte surface–targeted antisecretory drugs
Year: 2013
Type: article
Abstract: Secretory diarrheas such as cholera are a major cause of morbidity and mortality in developing countries. We previously introduced the concept of antisecretory therapy for diarrhea using chloride channel inhibitors targeting the cystic fibrosis transmembrane conductance regulator channel pore on the extracellular surface of enterocytes. However, a concern with this strategy is that rapid fluid secretion could cause convective drug washout that would limit the efficacy of extracellularly targeted inhibitors. Here, we developed a convection-diffusion model of washout in an anatomically accurate three-dimensional model of human intestine comprising cylindrical crypts and villi secreting fluid into a central lumen. Input parameters included initial lumen flow and inhibitor concentration, inhibitor dissociation constant (K(d)), crypt/villus secretion, and inhibitor diffusion. We modeled both membrane-impermeant and permeable inhibitors. The model predicted greatly reduced inhibitor efficacy for high crypt fluid secretion as occurs in cholera. We conclude that the antisecretory efficacy of an orally administered membrane-impermeant, surface-targeted inhibitor requires both (a) high inhibitor affinity (low nanomolar K(d)) to obtain sufficiently high luminal inhibitor concentration (>100-fold K(d)), and (b) sustained high luminal inhibitor concentration or slow inhibitor dissociation compared with oral administration frequency. Efficacy of a surface-targeted permeable inhibitor delivered from the blood requires high inhibitor permeability and blood concentration (relative to K(d)).
Authors: Byung-Ju Jin, Jay R. Thiagarajah, A.S. Verkman
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1259071441, Role of airway submucosal glands in CF lung disease, Application of Novel Optical Methods to Cell Dynamics, G3011728751, G3102004739, Application of Novel Optical Methods to Cell Dynamics, Aquaporin-4 in NMO Optic Neuritis: Pathogenesis and New Therapies, G3730553470, Mechanisms of water transport in renal epithelia, G4468004498, MECHANISMS OF WATER TRANSPORT IN RENAL EPITHELIA, Novel small-molecule therapies for CF
OpenAlex ID: W2027509369