Inhibitory effect of JTP-59557, a new triazole derivative, on intestinal phosphate transport in vitro and in vivo.
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.
Matsuo
Akira
A
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-Cho, Takatsuki, Osaka 569-1125, Osaka, Japan. akira.matsuo@ims.jti.co.jp
Negoro
Tamotsu
T
Seo
Tomohisa
T
Kitao
Yuki
Y
Shindo
Masanori
M
Segawa
Hiroko
H
Miyamoto
Ken-Ichi
K
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*
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