title: Modulating effect of polyethylene glycol on the intestinal transport and absorption of prednisolone, methylprednisolone and quinidine in rats by in-vitro and in-situ absorption studies.
abstract: The effects of polyethylene glycol 20000 (PEG 20000) on the intestinal absorption of prednisolone, methylprednisolone and quinidine, three P-glycoprotein (P-gp) substrates, across the isolated rat intestinal membranes were examined by an in-vitro diffusion chamber system. The serosal-to-mucosal (secretory) transport of these P-gp substrates was greater than their mucosal-to-serosal (absorptive) transport, indicating that their net movement across the intestinal membranes was preferentially in the secretory direction. The polarized secretory transport of these drugs was remarkably diminished and their efflux ratios decreased in the presence of PEG 20000. In addition, PEG 20000 did not affect the transport of Lucifer yellow, a non-P-gp substrate. The intestinal membrane toxicity of PEG 20000 was evaluated by measuring the release of alkaline phosphatase (ALP) and protein from the intestinal membranes. The release of ALP and protein was enhanced in the presence of 20 mM sodium deoxycholate (NaDC), a positive control, while these biological parameters did not change in the presence of 0.1-5% (w/v) PEG 20000. These findings indicated that the intestinal membrane damage caused by PEG 20000 was not a main reason for the enhanced absorptive transport of these P-gp substrates in the presence of PEG 20000. Furthermore, the transepithelial electrical resistance (TEER) of rat jejunal membranes in the presence or absence of PEG 20000 was measured by a diffusion chamber method. PEG 20000 (0.1-5.0 % w/v) did not change the TEER values of the rat jejunal membranes, indicating that the increase in the absorptive transport of these P-gp substrates might not be due to the increased transport of these P-gp substrates via a paracellular pathway caused by PEG 20000. Finally, the effect of PEG 20000 on the intestinal absorption of quinidine was examined by an in-situ closed-loop method. The intestinal absorption of quinidine was significantly enhanced in the presence of 0.1-1.0% (w/v) PEG 20000. These findings suggest that PEG 20000 might be a useful excipient to improve the intestinal absorption of quinidine, which is mainly secreted by a P-gp-mediated efflux system in the intestine.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi Yamashina-ku, Kyoto 607-8414 Japan.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shen
authors.forename: Wenji
authors.initials: W
authors.lastname: Li
authors.forename: Yulian
authors.initials: Y
authors.lastname: Lin
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Naoki
authors.initials: N
authors.lastname: Okada
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujita
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D003840:Deoxycholic Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D005079:Excipients / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D007408:Intestinal Absorption; D007546:Isoquinolines / Q000493:pharmacokinetics; D008297:Male; D008775:Methylprednisolone / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011239:Prednisolone / Q000493:pharmacokinetics*; D011802:Quinidine / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D018675:Toxicity Tests
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D005079:Excipients; D007546:Isoquinolines; D003840:Deoxycholic Acid; D011092:Polyethylene Glycols; C017475:lucifer yellow; D011239:Prednisolone; D000469:Alkaline Phosphatase; D011802:Quinidine; D008775:Methylprednisolone