title: Effects of Labrasol and other pharmaceutical excipients on the intestinal transport and absorption of rhodamine123, a P-glycoprotein substrate, in rats.
abstract: Effects of Labrasol and other pharmaceutical excipients on the intestinal transport and absorption of rhodamine123, a P-glycoprotein substrate (P-gp) were examined. Intestinal transport and absorption studies were examined by an in vitro diffusion chamber method and an in situ closed loop method. We evaluated the intestinal membrane damage produced by Labrasol by measuring the release of protein and alkaline phosphatase (ALP). Labrasol (0.075-0.1% (v/v)) increased the absorptive transport of rhodamine123 and decreased its secretory transport in the in vitro transport studies. However, Labrasol did not change the transport of Lucifer yellow, a non-P-gp substrate, suggesting that the effect of Labrasol on the transport of drugs was specific for rhodamine123. We observed almost no intestinal membrane damage in the presence of Labrasol. These findings suggest that the increase in the absorptive transport of rhodamine123 in the presence of Labrasol may not be due to its intestinal membrane damage. In the in situ absorption studies, we found that Labrasol (0.1% (v/v)) significantly enhanced the intestinal absorption of rhodamine123 in rats, although the absorption enhancing effect of Labrasol was much less than that of verapamil. These findings suggest that low concentrations of Labrasol might inhibit the function of P-gp in the intestine, thereby increasing intestinal absorption and bioavailability of P-gp substrates including rhodamine123. However, we may also consider the contribution to the enhanced intestinal absorption of rhodamine123 via a passive transport in addition to the inhibitory action of Labrasol for the function of P-gp in the intestine.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Kyoto, Japan.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Lin
authors.forename: Qi
authors.initials: Q
authors.lastname: Shen
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Naoki
authors.initials: N
authors.lastname: Okada
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujita
authors.forename: Xuehua
authors.initials: X
authors.lastname: Jiang
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000494:pharmacology; D005079:Excipients / Q000494:pharmacology*; D005989:Glycerides; D007082:Ileum / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D009930:Organic Chemicals / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005026:Ethylene Glycols; D005079:Excipients; D005989:Glycerides; D009930:Organic Chemicals; C440220:Labrasol; C104509:gelucire 44-14; D020112:Rhodamine 123; D011092:Polyethylene Glycols; C010111:carbitol; D000469:Alkaline Phosphatase