Investigation of Endogenous Compounds for Assessing the Drug Interactions in the Urinary Excretion Involving Multidrug and Toxin Extrusion Proteins

详细信息    查看全文

• 作者：Koji Kato (1)
  Haruyuki Mori (1)
  Tomoko Kito (2)
  Miyu Yokochi (2)
  Sumito Ito (2)
  Katsuhisa Inoue (3)
  Atsushi Yonezawa (4)
  Toshiya Katsura (4)
  Yuji Kumagai (5)
  Hiroaki Yuasa (3)
  Yoshinori Moriyama (6)
  Ken-ichi Inui (7)
  Hiroyuki Kusuhara (2)
  Yuichi Sugiyama (2) (8)
  
• 关键词：drug interaction ; metabolomics ; multidrug and toxin extrusion protein ; organic cation ; tubular secretion
• 刊名：Pharmaceutical Research
• 出版年：2014
• 出版时间：January 2014
• 年：2014
• 卷：31
• 期：1
• 页码：136-147
• 全文大小：
• 作者单位：Koji Kato (1)
  Haruyuki Mori (1)
  Tomoko Kito (2)
  Miyu Yokochi (2)
  Sumito Ito (2)
  Katsuhisa Inoue (3)
  Atsushi Yonezawa (4)
  Toshiya Katsura (4)
  Yuji Kumagai (5)
  Hiroaki Yuasa (3)
  Yoshinori Moriyama (6)
  Ken-ichi Inui (7)
  Hiroyuki Kusuhara (2)
  Yuichi Sugiyama (2) (8)
  
  1. Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan
  2. Laboratory of Molecular Pharmacokinetics Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
  3. Department of Biopharmaceutics Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
  4. Department of Pharmacy, Kyoto University Hospital, Kyoto, Japan
  5. Clinical Trial Center, Kitasato University East Hospital, Kanagawa, Japan
  6. Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, & Pharmaceutical Sciences, Okayama, Japan
  7. Kyoto Pharmaceutical University, Kyoto, Japan
  8. Sugiyama Laboratory, RIKEN Innovation Center Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, 230-0045, Japan
  
• ISSN：1573-904X

文摘

Purpose Multidrug and toxin extrusion proteins (MATEs) are multispecific organic cation transporters mediating the efflux of various cationic drugs into the urine. The present study aimed at identifying endogenous compounds in human plasma and urine specimens as biomarkers to evaluate drug interactions involving MATEs in the kidney without administration of their exogenous probe drugs. Methods An untargeted metabolomic analysis was performed using urine and plasma samples from healthy volunteers and mice treated with or without the potent MATE inhibitor, pyrimethamine. Plasma and urinary concentrations of candidate markers were measured using liquid chromatography-mass spectrometry. Transport activities were determined in MATE- or OCT2-expressing HEK293 cells. The deuterium-labeled compounds of candidates were administered to mice for pharmacokinetics study. Results Urinary excretion of eleven compounds including thiamine and carnitine was significantly lower in the pyrimethamine-treatment group in humans and mice, whereas no endogenous compound was noticeably accumulated in the plasma. The renal clearance of thiamine and carnitine was decreased by 70%4% and 90%4% (p<0.05), respectively, in human. The specific uptake of thiamine was observed in MATE1-, MATE2-K- or OCT2-expressing HEK293 cells with Km of 3.51.0, 3.90.8 and 59.96.7, respectively. The renal clearance of carnitine-d 3 was decreased by 62% in mice treated with pyrimethamine. Conclusions Our findings indicate that MATEs account for the efflux of thiamine and perhaps carnitine as well as drugs into the urine. The urinary excretion of thiamine is useful to detect drug interaction involving MATEs in the kidney.