title: Changes of Absorptive and Secretory Transporting System of (1 → 3) β-D-glucan Based on Efflux Transporter in Indomethacin-induced Rat.
abstract: Infection and inflammation suppress the expression and activity of several drug transporters in liver. In the intestine, P-glycoprotein (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) are important barriers to the absorption of many clinically important drugs. The expression and activity of these proteins were examined under inflammation. Drug transport was determined in jejunum and ileum segments isolated from 1.0 mg/kg, 5.0 mg/kg, and 7.5 mg/kg indomethacin-treated or control rats in diffusion chambers. Transport of laminaran, used as a model compound of (1-3) β-D-glucan, was measured for 120 min in the presence or absence of inhibitors. Reverse transcription-polymerase chain reaction was used to measure mRNA levels. Compared with controls, levels of Mdr1a mRNA were significantly decreased in the jejunum and ileum of 7.5 mg/kg indomethacin-treated rats. Both reductions in the basolateral to apical efflux of laminaran and increases in the apical to basolateral influx of laminaran were observed, resulting in significant increases in the apical to basolateral absorption of laminaran in 7.5 mg/kg indomethacin-treated rats. The inhibitory effect of verapamil on laminaran transport was observed in control rats but not in indomethacin-treated rats. Fluorescein isothiocyanate dextran 40,000 permeability, membrane resistance, and claudin-4 mRNA level were not altered, indicating no change in the paracellular pathway. These results indicate that indomethacin-induced inflammation reduces the intestinal expression and activity of P-gp in rats, which elicits corresponding changes in the intestinal transport of laminaran. Hence, inflammatory diseases may impose variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters.
authors: Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors: Aiko
authors: A
authors: Iida
authors: Shohei
authors: S
authors: Ouchi
authors: Toshio
authors: T
authors: Oda
authors: Jun
authors: J
authors: Aketagawa
authors: Yasuhiko
authors: Y
authors: Ito
authors: Yusuke
authors: Y
authors: Takizawa
authors: Mikio
authors: M
authors: Tomita
authors: Masahiro
authors: M
authors: Hayashi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D004195:Disease Models, Animal; D015536:Down-Regulation; D005936:Glucans / Q000378:metabolism; D007082:Ileum / Q000378:metabolism*; D007213:Indomethacin; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D011509:Proteoglycans; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013997:Time Factors; D047071:beta-Glucans / Q000378:metabolism*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; C489249:Abcg2 protein, rat; D005936:Glucans; D011509:Proteoglycans; D012333:RNA, Messenger; D047071:beta-Glucans; C010770:polysaccharide-K; C008247:laminaran; C095122:multidrug resistance protein 3; D007213:Indomethacin