Pharmaceutical Excipients Enhance Intestinal Absorption Of Ganciclovir

P-glycoprotein (P-gp) is a kind of membrane transporter pumping a wide spectrum of its substrates and xenobiotics out of cells. Located in the apical membrane of the epithelium, it plays an important role in limiting drug absorption in intestine. At present, it is an innovative strategy to improve drug absorption and consequently oral bioavailability by inhibiting the efflux function of P-gp.In rats we examined the effects of some excipients on the intestinal absorption of ganciclovir (GCV), a BCS-III drug and substrate of P-gp, by assessing its in vitro transfer (mucosa to serosa) and in situ transepithelial permeation. In vitro, all selected excipients (concentration range 0.1 to 1 % [w/v]) could increase the transport amount of GCV in the everted gut sac model. Whereas enhancement by F-68 demonstrated regional differences like verapamil, PEG-400, Tween-80 and EL-35 exhibited no regional differences. In situ studies were performed by an improved perfusion model, single-pass perfusion with whole small intestine, to measure the permeability of lipophobic compounds more accurately. The permeability of GCV was significantly increased: its intestinal Peff was enhanced from 2.35×10-6 cm·s-1 by 1.8~5.1-fold (F-68), 2.6~4.8-fold (PEG-400), 2.8-fold (Tween-80) and 6.7~13.4-fold (EL-35). The effects of EL-35 and F-68 were dose-dependent but those of PEG-400 and Tween-80 were not. The results suggest that absorption enhancements of GCV by these excipients are probably due to inhibition of P-gp-mediated drug efflux. It could be deduced from their different properties that both blocking binding sites of P-gp and altering membrane fluidity were involved in their P-gp-inhibition. The former mechanism might be involved for F-68, while the latter one might account for the effects of PEG-400, Tween-80 and EL-35.