Involvement of Organic Cation Transporters in the Clearance and Milk Secretion of Thiamine in Mice

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• 作者：Koji Kato ; Chihiro Moriyama ; Naoki Ito ; Xuan Zhang…
• 关键词：multidrug and toxin extrusion protein ; organic cation transporter ; thiamine ; vitamin b1
• 刊名：Pharmaceutical Research
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：32
• 期：7
• 页码：2192-2204
• 全文大小：1,162 KB
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  anched fatty acids. Proc Natl Acad Sci U S A. 1999;96(18):10039-4.View Article PubMed Central PubMed
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  13.Rabbani N, Alam SS, Riaz S, Larkin JR, Akhtar MW, Shafi T, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia. 2009;52(2):208-2.View Article PubMed
  14.Dutta B, Huang W, Molero M, Kekuda R, Leibach FH, Devoe LD, et al. Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem. 1999;274(45):31925-.View Article PubMed
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  22.Zeng
• 作者单位：Koji Kato (1)
  Chihiro Moriyama (2)
  Naoki Ito (3)
  Xuan Zhang (2)
  Kenji Hachiuma (1)
  Naoko Hagima (1)
  Katsuya Iwata (1)
  Jun-ichi Yamaguchi (1)
  Kazuya Maeda (2)
  Kousei Ito (4)
  Hiroshi Suzuki (5)
  Yuichi Sugiyama (6)
  Hiroyuki Kusuhara (2)
  
  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, 7-3-1, Hongo Bunkyo-ku, Tokyo, 113-0033, Japan
  3. Department of Pediatrics, The University of Tokyo Hospital Faculty of Medicine, The University of Tokyo, Tokyo, Japan
  4. Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan
  5. Department of Pharmacy, The University of Tokyo Hospital Faculty of Medicine, The University of Tokyo, Tokyo, Japan
  6. Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Pharmacy
  Biochemistry
  Medical Law
  Biomedical Engineering
  
• 出版者：Springer Netherlands
• ISSN：1573-904X

文摘

Purpose To investigate the role of organic cation transporters (Octs) and multidrug and toxin extrusion protein 1 (Mate1) in the disposition of thiamine. Methods The uptake of [3H]thiamine was determined in Oct1-, Oct2-, and Oct3-expressing HEK293 cells and freshly isolated hepatocytes. A pharmacokinetic study of thiamine-d ₃ following intravenous infusion (1 and 100?nmol/min/kg) was conducted in male Oct1/2(+/+) and Oct1/2(?? mice. A MATE inhibitor, pyrimethamine, (5?mg/kg) was administered intravenously. The plasma and breast milk concentrations of thiamine were determined in female mice. Results Thiamine is a substrate of Oct1 and Oct2, but not Oct3. Oct1/2 defect caused a significant reduction in the uptake of [3H]thiamine by hepatocytes in vitro, and elevated the plasma thiamine concentration by 5.8-fold in vivo. The plasma clearance of thiamine-d ₃ was significantly decreased in Oct1/2(?? mice. At the higher infusion rate of 100?nmol/min/kg thiamine-d ₃, Oct1/2 defect or pyrimethamine-treatment caused a significant reduction in the renal clearance of thiamine-d ₃. The total thiamine and thiamine-d ₃ concentrations were moderately reduced in the intestine of Oct1/2(?? mice but were unchanged in the kidney, liver, or brain. The milk-to-plasma concentration ratio of thiamine was decreased by 28-fold in the Oct1/2(?? mice. Conclusions Oct1 is possibly responsible for the plasma clearance of thiamine via tissue uptake and for milk secretion. Oct1/2 and Mate1 are involved in the renal tubular secretion of thiamine.