Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies.
We examined the effect of polyethylene glycols (PEGs) with different molecular weights and their derivatives on the intestinal absorption of rhodamine123, a P-glycoprotein (P-gp) substrate, across the isolated rat intestinal membranes by an in vitro diffusion chamber system. The serosal to mucosal (secretory) transport of rhodamine123 was greater than its mucosal to serosal (absorptive) transport, indicating that the net movement of rhodamine123 across the intestinal membranes was preferentially secretory direction. The secretory transport of rhodamine123 was inhibited by the addition of PEGs with average molecular weights of 400, 2000 and 20,000, irrespective of its molecular weight. The inhibitory effects of these PEGs for the intestinal P-gp function were concentration dependent over the range 0.1-20% (v/v or w/v). Similar inhibitory effect for the intestinal P-gp function was observed when PEG derivatives including PEG monolaurate, PEG monooleate and PEG monostearate were added to the mucosal site of the chambers. Furthermore, we also examined effect of PEG20,000 on the intestinal absorption of rhodamine123 by an in situ closed loop method. The intestinal absorption of rhodamine123 was enhanced in the presence of PEG20,000. These findings suggest that PEGs and their derivatives are useful excipients to inhibit the function of intestinal P-gp, thereby improving the intestinal absorption of P-gp substrates, which are secreted by a P-gp-mediated efflux system.
Shen
Qi
Q
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Kyoto 607-8414, Japan.
Lin
Yulian
Y
Handa
Takahiro
T
Doi
Masamichi
M
Sugie
Masami
M
Wakayama
Kana
K
Okada
Naoki
N
Fujita
Takuya
T
Yamamoto
Akira
A
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002626:Chemistry, Pharmaceutical; D015194:Diffusion Chambers, Culture; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000737:chemistry / Q000494:pharmacology*; D007408:Intestinal Absorption; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000493:pharmacokinetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D005079:Excipients; D020112:Rhodamine 123; D011092:Polyethylene Glycols