COMPARISON OF HT29-18-C-1 AND CACO-2 CELL-LINES AS MODELS FOR STUDYING INTESTINAL PARACELLULAR DRUG ABSORPTION

Purpose. To compare the permeability characteristics of HT29-18-C-1 co lonic epithelial cell line with Caco-2, an established model of intest inal drug transport. Methods, Cell lines were grown as epithelial mono layers. Permeability was measured over a range of transepithelial elec trical resistance (R(t)) using a group of drug compounds. Results, HT2 9-18-C-1 develop R(t) slowly when grown in culture, allowing permeabil ity to be measured over a wide range (80-600 Omega . cm(2)). In contra st, Caco-2 monolayers rapidly develop R(t) of approximate to 300 Omega . cm(2) and require Ca2+-chelation to generate R(t) equivalent to hum an intestine (60-120 Omega . cm(2)). Permeability of atenolol, ranitid ine, cimetidine, hydrochlorothiazide and mannitol across HT29-18-C-1 d ecreased 4-5 fold as R(t) developed from 100-300 Omega(2) . cm(2) indi cating they permeate via the paracellular route. In contrast, ondanset ron showed no difference in permeability with changing R(t) consistent with transcellular permeation. Permeability profiles across low R(t) HT29-18C(1) and pulse EGTA-treated Caco-2 monolayers were the same for all 5 paracellular drugs suggesting that transient Ca2+ removal does not alter selectivity of the tight junctions. Permeabilities of cimeti dine, hydrochlorothiazide and atenolol across 100 Omega . cm(2) HT29-1 8-C-1 monolayers reflect more closely those reported for the human ile um in vivo than did mature Caco-2 monolayers. Conclusions. HT29-18-C-1 monolayers can be used to study drug permeability at R(t) values simi lar to human intestine without the need for Ca2+ chelation. As such, t hey offer a useful alternative to Caco-2 for modelling intestinal drug absorption.