The effects of common solubilizing agents on the intestinal membrane barrier functions and membrane toxicity in rats.

The use of solubilizing agents to improve the solubility of poorly water-soluble drugs often results in an alteration of intestinal membrane barrier function and intestinal membrane damage. In this study, 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextran (MW 4400, FD4) were used as model compounds to examine the effects of twelve common solubilizing agents, sodium taurocholate (NaTC), Labrasol, polyethylene glycol 400 (PEG 400), Transcutol P, propylene glycol, Gelucire 44/14, HCO-60, ethanol, Cremophor EL, Tween 80, 2 hydroxypropyl-beta-cyclodextrin (2HP-beta-CyD) and dimethylsulfoxide (DMSO), on intestinal membrane barrier function and membrane toxicity in rats. Intestinal transport and absorption of CF were examined using an in vitro diffusion chamber and an in situ closed-loop technique. The in vitro diffusion chamber study showed that only 5 and 10% (w/v) NaTC significantly increased the transport of CF across the intestinal membrane. The in situ closed-loop study showed a remarkable increase in the absorption of CF and a bioavailability of more than 30% in the presence of 5 and 10% (v/v) Labrasol, 5 and 10% (w/v) NaTC and 10% (v/v) Transcutol P. Furthermore, we evaluated the effect of NaTC and Labrasol on the intestinal absorption of FD4, a high molecular weight compound. The results indicated that the absorption of FD4 also increased in the presence of 5 and 10% (w/v) NaTC and 10% (v/v) Labrasol, suggesting that these concentrations of NaTC and Labrasol may alter the intestinal membrane barrier functions in rats. We measured the release of protein and lactate dehydrogenase (LDH) from the intestinal membrane to examine the safety of solubilizing agents in the intestine. 5 and 10% (w/v) NaTC and 5 and 10% (v/v) Gelucire 44/14 significantly increased the presence of these toxicity markers compared to the control. The LDH level was also increased in the presence of 10% (v/v) of Cremophor EL. These findings suggest that the solubilizing agents at these concentrations except for NaTC, Gelucire 44/14 and Cremophor EL are considered safe and do not cause intestinal membrane damage. In conclusion, this study provides a basic approach in screening and predicting the effects of solubilizing agents for intestinal absorption studies using drugs poorly soluble in water.