Carrier-mediated hepatic uptake of a novel nonrenal excretion type uric acid generation inhibitor, Y-700.
Y-700, a novel xanthine oxidase inhibitor, was recently developed for the treatment of hyperuricemia and gout. Since the major elimination route of this compound is hepatic metabolism and excretion, the aim of the present study was to characterize the uptake mechanism of Y-700 in the liver, which is also the pharmacological target of Y-700. Efficient uptake of Y-700 was observed both in the liver in vivo and in isolated rat hepatocytes. The uptake was Na(+)-dependent, saturable and inhibited both by ATP-depressants and various organic anions. Indomethacin competitively inhibited Y-700 uptake, whereas the inhibitory effect of organic cations and nucleosides was not so remarkable. Saturable and Na(+)-dependent uptake of Y-700 was also observed in freshly isolated human hepatocytes. Uptake of Y-700 by sinusoidal membrane transporters, such as organic anion transporter (Oat) 2 and organic anion transporting polypeptide (OATP)-B, OATP-C, OATP-8, and Oatp1, could not be detected although uptake of Y-700 in the oocytes expressing sodium/taurocholate cotransporting polypeptide (NTCP) was slightly observed. In conclusion, active transport system(s), which specifically recognize certain types of anionic compounds, are involved in the hepatic uptake of Y-700 and, at least partially, relevant to its elimination from the circulation as well as delivery to pharmacological target.
Sai
Yoshimichi
Y
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Japan.
Kato
Yukio
Y
Nakamura
Keiko
K
Kato
Sayaka
S
Nishimura
Tomohiro
T
Kubo
Yoshiyuki
Y
Tamai
Ikumi
I
Yang
Shu
S
Hu
Zhuhan
Z
Yamada
Ichimaro
I
Tsuji
Akira
A
D000818:Animals; D002250:Carbon Radioisotopes; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D026901:Membrane Transport Proteins / Q000494:pharmacology; D008845:Microinjections; D009865:Oocytes / Q000187:drug effects; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters; D014981:Xenopus
C433950:1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid; D002250:Carbon Radioisotopes; D026901:Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D011720:Pyrazoles; C088800:Slc22a7 protein, rat; D027981:Symporters; C071908:sodium-bile acid cotransporter