Common solubilizers to estimate the Caco-2 transport of poorly water-soluble drugs

Solubilizers are often used to enhance the bioavailability of drugs with poor aqueous solubility. This study focuses on the use of the Caco-2 system containing solubilizers to predict the absorption of poorly water-soluble drugs in humans. First, the effects of propylene glycol (PG), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), polyethylene glycol 400 (PEG 400), and Tween 80 on the viability (transepithelial electrical resistance, TEER) of 3-day cultured Caco-2 monolayers were evaluated. These solubilizers, even at the low concentration, reduce the viability of Caco-2 monolayers; these results indicate the impossibility for 3-day cultured Caco-2 monolayers to be used for this test. Next, the effects of PG, Tween 80, PEG 400, HP-beta-CD, Pluronic F-68 (Pluronic), HCO-40, sodium lauryl sulfate (SLS), Gelucire 44/14, Transcutol P, and extract gall powder on the viability of 21-day cultured Caco-2 monolayers and the apparent permeability (P-app) of propranolol (PPL), Nadolol (NDL), and FITC-dextran 4000 (FD-4) were investigated. Five different solubilizing methods (20% PG, 5% Tween 80, 5% PEG 400, 5% HP-beta-CD, and 5% Tween 80 + 5% PEG 400) did not affect the viability of 21-day cultured Caco-2 monolayers. Furthermore, the P-app values of the three compounds containing these solubilizers did not differ from the values for control formulations (without solubilizers). These results clearly suggest that the use of PG, Tween 80, PEG 400, or HP-beta-CD as solubilizing excipients and the testing of these formulations on 21-day cultured Caco-2 monolayers can predict intestinal absorption of poorly water-soluble drugs in humans. (C) 2002 Elsevier Science B.V. All rights reserved.