title: Inhibitory effect of JTP-59557, a new triazole derivative, on intestinal phosphate transport in vitro and in vivo.
abstract: JTP-59557 [(-)-4-(2-tert-Butyl-4,5-dichlorophenyl)-5-(5-trifluoromethylpyridin-2-ylsulfanyl)-4H-[1,2,4]triazol-3-ol] showed an inhibitory effect on Na(+)-dependent inorganic phosphate (Pi) transport in intestinal brush border membrane vesicles with an IC(50) value of 0.40 microM in rabbit and with an IC(50) of 0.19 microM in rat, without affecting Na(+)-independent Pi and Na(+)-dependent d-glucose transport activities. In Chinese hamster ovary (CHO) cells expressing human type IIb Na/Pi cotransporter (type IIb), JTP-59557 decreased human type IIb-mediated Pi uptake with an IC(50) of 0.12 microM. In rabbit intestinal brush border membrane vesicles, JTP-59557 behaved as a noncompetitive inhibitor with respect to Pi. In an in vivo study, single administration of JTP-59557 significantly decreased the intestinal Pi absorption rate, when either Pi solution or laboratory chow was given to rats. In this report, we show that JTP-59557 is a potent, selective, stereospecific, noncompetitive inhibitor of intestinal Na/Pi cotransporters including type IIb, and it may represent a new class of intestinal Pi absorption inhibitor.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-Cho, Takatsuki, Osaka 569-1125, Osaka, Japan. akira.matsuo@ims.jti.co.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuo
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Negoro
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Seo
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kitao
authors.forename: Masanori
authors.initials: M
authors.lastname: Shindo
authors.forename: Hiroko
authors.initials: H
authors.lastname: Segawa
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D017245:Foscarnet / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000601:surgery; D007700:Kinetics; D008026:Ligation; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D010710:Phosphates / Q000493:pharmacokinetics*; D016226:Phosphorus, Dietary / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D050608:Sodium-Phosphate Cotransporter Proteins; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C503785:JTP-59557; D010710:Phosphates; D016226:Phosphorus, Dietary; C493557:SLC34A2 protein, human; C493559:Slc34a2 protein, rat; D050608:Sodium-Phosphate Cotransporter Proteins; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; D027981:Symporters; D014230:Triazoles; D017245:Foscarnet