Biol. Pharm. Bull. 30(7) 1301—1307 (2007)

of about 170 kDa that belongs to the superfamily of ATPbinding cassette (ABC) transporters. P-gp is extensively expressed in tumor cells, liver, intestinal brush border membranes, kidney, brain, and adrenal glands. It can actively pump drugs out of cells, thus reducing the oral bioavailability of a wide range of drugs such as digoxin, vinca alkaloids, and b-adrenergic agonists. It has been reported that some P-glycoprotein inhibitors such as verapamil and cyclosporin A could enhance the bioavailability of P-gp substrate drugs. But it is well known that these drugs themselves have pharmacological activities. Therefore, it is important to find a P-gp inhibitor which does not have pharmacological activities. It has been demonstrated that a number of excipients could inhibit the function of P-gp, thereby increasing the absorption of P-gp substrate drugs. These excipients include polyethylene glycols (PEGs), nonionic surfactants, fatty acids and bile salts. It has been reported that several excipients such as Cremophor EL, Tween 80, n-lauryl-b-D-maltopyranoside (LM), Pluronic P85, vitamin E-TPGS, PEGs, sodium caprate and dimethyl-b-cyclodextrin could inhibit the function of Pgp by in vitro and in vivo methods. Among these pharmaceutical excipients, Labrasol is one which has been widely used for the solubilization of hydrophobic drugs. Labrasol is obtained from coconut oil and has very low toxicity with an LD50 of 22 g/kg for rats. Recently, it was reported that Labrasol had a strong absorption enhancing effect and that intestinal absorption of various poorly absorbable drugs including gentamicin, insulin and vancomycin was enhanced in its presence. However, few studies examined the effect of Labrasol on the function of P-gp in the intestine and the intestinal absorption of P-gp substrates. Cornaire et al. (2004) examined the effect of Labrasol on the transport of digoxin by an in vitro everted sac experiment, and reported that 0.5% Labrasol increased the transport of digoxin in this experiment. However, they demonstrated that 0.5% Labrasol could increase the lactate dehydrogenase (LDH), and so the increase in digoxin transport might be due to the intestinal membrane damage, and not to the inhibition of P-gp function in the intestine. Furthermore, they did not study the different regional effects of Labrasol on the transport of P-gp substrate and in situ or in vivo intestinal absorption of P-gp substrate with or without Labrasol. In this study, therefore, we studied the effect of Labrasol on the function of P-gp using two different intestinal absorption experiments. We first adopted an in vitro diffusion chamber system using the isolated rat intestinal membrane to evaluate the effects of Labrasol and other pharmaceutical excipients, Gelucire44/14 and Transcutol P on the intestinal transport of rhodamine123, a P-gp substrate. In addition, the intestinal membrane damage of Labrasol was evaluated by measuring the release of alkaline phosphatase (ALP) and protein as biological markers. Finally, we also investigated the effects of Labrasol on the intestinal absorption of rhoJuly 2007 1301