Excipients enhance intestinal absorption of ganciclovir by P-gp inhibition: assessed in vitro by everted gut sac and in situ by improved intestinal perfusion.
In rats we examined the effects of some common excipients on the intestinal absorption of ganciclovir (GCV), a BCS-III drug and substrate of P-gp, by assessing its in vitro transfer from mucosa to serosa and in situ transepithelial permeation. In vitro, all selected excipients (concentration range 0.1-1% [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 determine more accurately the permeability of lipophobic compounds. The permeability of GCV was significantly increased by all excipients. 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 enhancements of intestinal absorption 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.
Li
Ming
M
Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China.
Si
Luqin
L
Pan
Hongping
H
Rabba
Abdullah K
AK
Yan
Fang
F
Qiu
Jun
J
Li
Gao
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport; D002851:Chromatography, High Pressure Liquid; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology*; D015774:Ganciclovir / Q000737:chemistry / Q000493:pharmacokinetics*; D005947:Glucose / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008954:Models, Biological; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000998:Antiviral Agents; D005079:Excipients; D005947:Glucose; D015774:Ganciclovir