Enhanced Permeability of Etoposide across Everted Sacs of Rat Small Intestine by Vitamin E-TPGS

摘要

Etoposide, a widely used anticancer drug, exhibits low and variable oral bioavailability mainly because of being substrate for the efflux transporter, P-glycoprotein (P-gp). Therefore, the present study was aimed to investigate the effect of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and PEG 400 as P-gp inhibitors on the intestinal absorption of etoposide. Everted sacs of rat small intestine were incubated in Krebs buffer solution which contained etoposide in the absence or presence of various concentrations of TPGS or PEG 400. The effect of verapamil as a known P-gp inhibitor on the absorption of drug was also studied. The absorptive transport of etoposide was significantly enhanced (p < 0.001) in the presence of verapamil (100 μg/mL) and TPGS (over the concentration range of 0.002- 0.1 mg/mL), suggesting that the inhibition of P-gp located in the intestine may be involved in the enhancement of etoposide absorption. However, the addition of PEG 400 at various concentrations (0.05, 0.1 and 0.5% w/v) had no effect on the etoposide transport. No significant difference was found between the permeability values in the absence and presence of the maximum concentration of TPGS for two transport markers, lucifer yellow and imipramine, indicating that the enhancement in etoposide permeability in the presence of TPGS was not due to the compromise in tight junctions or membrane integrity of epithelial cells. The results of the study suggest that the use of TPGS as a safe excipient in etoposide formulations may enhance the oral bioavailability of etoposide and result in a predictable oral absorption.