PURPOSE: To assess the contribution of organic anion transporting polypeptide 1a5 (Oatp1a5/Oatp3) in the intestinal absorption of an orally active endothelin receptor antagonist, (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylene-dioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (compound-A) in rats. METHODS: Uptakes of [(14)C]compound-A by Oatp1a5-expressing Xenopus laevis oocytes and isolated rat enterocytes were evaluated. RESULTS: The uptake of compound-A by Oatp1a5-expressing oocytes was significantly higher than that by water-injected oocytes and Oatp1a5-mediated uptake was saturable with K(m) value of 116 microM. Compound-A was taken up into isolated enterocytes in time- and concentration-dependent manners and the estimated K(m) value was 83 microM, which was close to that for the Oatpt1a5-mediated uptake in oocytes. Both uptakes of compound-A by Oatp1a5-expressing oocytes and enterocytes were pH-sensitive with significantly higher uptake at acidic pH than those at neutral pH. Uptakes of compound-A into Oatp1a5-expressing oocytes and enterocytes were significantly decreased in the presence of Oatp1a5 substrates such as bromosulfophthalein and taurocholic acid. CONCLUSIONS: These results consistently suggested that Oatp1a5 is contributing to the intestinal absorption of compound-A at least in part, and the transporter-mediated absorption seems to be maximized at the acidic microenvironment of epithelial cells in the small intestine in rats.
PURPOSE: To assess the contribution of organic anion transporting polypeptide 1a5 (Oatp1a5/Oatp3) in the intestinal absorption of an orally active endothelin receptor antagonist, (+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylene-dioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (compound-A) in rats. METHODS: Uptakes of [(14)C]compound-A by Oatp1a5-expressing Xenopus laevis oocytes and isolated rat enterocytes were evaluated. RESULTS: The uptake of compound-A by Oatp1a5-expressing oocytes was significantly higher than that by water-injected oocytes and Oatp1a5-mediated uptake was saturable with K(m) value of 116 microM. Compound-A was taken up into isolated enterocytes in time- and concentration-dependent manners and the estimated K(m) value was 83 microM, which was close to that for the Oatpt1a5-mediated uptake in oocytes. Both uptakes of compound-A by Oatp1a5-expressing oocytes and enterocytes were pH-sensitive with significantly higher uptake at acidic pH than those at neutral pH. Uptakes of compound-A into Oatp1a5-expressing oocytes and enterocytes were significantly decreased in the presence of Oatp1a5 substrates such as bromosulfophthalein and taurocholic acid. CONCLUSIONS: These results consistently suggested that Oatp1a5 is contributing to the intestinal absorption of compound-A at least in part, and the transporter-mediated absorption seems to be maximized at the acidic microenvironment of epithelial cells in the small intestine in rats.
Authors: T Nishio; H Adachi; R Nakagomi; T Tokui; E Sato; M Tanemoto; K Fujiwara; M Okabe; T Onogawa; T Suzuki; D Nakai; K Shiiba; M Suzuki; H Ohtani; Y Kondo; M Unno; S Ito; K Iinuma; K Nunoki; S Matsuno; T Abe Journal: Biochem Biophys Res Commun Date: 2000-09-07 Impact factor: 3.575
Authors: I Tamai; Y Sai; A Ono; Y Kido; H Yabuuchi; H Takanaga; E Satoh; T Ogihara; O Amano; S Izeki; A Tsuji Journal: J Pharm Pharmacol Date: 1999-10 Impact factor: 3.765
Authors: Tian Lan; Anuradha Rao; Jamie Haywood; Charles B Davis; Chao Han; Eric Garver; Paul A Dawson Journal: Drug Metab Dispos Date: 2009-09-09 Impact factor: 3.922
Authors: John F Bowyer; Tucker A Patterson; Upasana T Saini; Joseph P Hanig; Monzy Thomas; Luísa Camacho; Nysia I George; James J Chen Journal: BMC Genomics Date: 2013-03-05 Impact factor: 3.969