- 著者
- Hiroshi Arakawa Natsumi Amezawa Yu Kawakatsu Ikumi Tamai
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Biological and Pharmaceutical Bulletin (ISSN:09186158)
- 巻号頁・発行日
- vol.43, no.11, pp.1792-1798, 2020-11-01 (Released:2020-11-01)
- 参考文献数
- 42
- 被引用文献数
- 10
Xanthine and hypoxanthine are intermediate metabolites of uric acid and a source of reactive oxidative species (ROS) by xanthine oxidoreductase (XOR), suggesting that facilitating their elimination is beneficial. Since they are reabsorbed in renal proximal tubules, we investigated their reabsorption mechanism by focusing on the renal uric acid transporters URAT1 and GLUT9, and examined the effect of clinically used URAT1 inhibitor on their renal clearance when their plasma concentration is increased by XOR inhibitor. Uptake study for [3H]xanthine and [3H]hypoxanthine was performed using URAT1- and GLUT9-expressing Xenopus oocytes. Transcellular transport study for [3H]xanthine was carried out using Madin–Darby canine kidney (MDCK)II cells co-expressing URAT1 and GLUT9. In in vivo pharmacokinetic study, renal clearance of xanthine was estimated based on plasma concentration and urinary recovery. Uptake by URAT1- and GLUT9-expressing oocytes demonstrated that xanthine is a substrate of URAT1 and GLUT9, while hypoxanthine is not. Transcellular transport of xanthine in MDCKII cells co-expressing URAT1 and GLUT9 was significantly higher than those in mock cells and cells expressing URAT1 or GLUT9 alone. Furthermore, dotinurad, a URAT1 inhibitor, increased renal clearance of xanthine in rats treated with topiroxostat to inhibit XOR. It was suggested that xanthine is reabsorbed in the same manner as uric acid through URAT1 and GLUT9, while hypoxanthine is not. Accordingly, it is expected that treatment with XOR and URAT1 inhibitors will effectively decrease purine pools in the body and prevent cell injury due to ROS generated during XOR-mediated reactions.
- 著者
- Ikumi TAMAI
- 出版者
- 日本薬物動態学会 会長/日本薬物動態学会 DMPK編集委員長
- 雑誌
- Drug Metabolism and Pharmacokinetics (ISSN:13474367)
- 巻号頁・発行日
- vol.28, no.6, pp.451-452, 2013 (Released:2013-12-25)
- 参考文献数
- 13
- 被引用文献数
- 1
- 著者
- AKIRA TSUJI HIDEKI HIROOKA IKUMI TAMAI TETSUYA TERASAKI
- 出版者
- JAPAN ANTIBIOTICS RESEARCH ASSOCIATION
- 雑誌
- The Journal of Antibiotics (ISSN:00218820)
- 巻号頁・発行日
- vol.39, no.11, pp.1592-1597, 1986 (Released:2006-04-19)
- 参考文献数
- 18
- 被引用文献数
- 12 16
Transport of a new cephalosporin developed for oral use, FK089, has been studied with the rat everted small intestine in vitro. Uptake was found to be pH-dependent with the maximum rate at an acidic pH below 5 and with a 5-fold lower rate at pH 7.0. The shape of the pH-rate profile was very similar to that of cefixime and different from that of pH-lipophilicity profile of FK089. The saturation kinetics of the uptake of FK089 were demonstrated at pH 5.0. By correcting the nonsaturable rate process, the kinetics of the mutual inhibition of FK089 uptake by cefixime and cefixime uptake by FK089 were all consistent with competitive type inhibition. The results indicate that carrier-mediated transport is responsible for transport of cephem antibiotics without an α-amino group in the side chain at the 7-position of the cephem nucleus in the intestinal brush-border membrane.