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Pharmaceutical Research

, Volume 32, Issue 7, pp 2192–2204 | Cite as

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

  • Koji Kato
  • Chihiro Moriyama
  • Naoki Ito
  • Xuan Zhang
  • Kenji Hachiuma
  • Naoko Hagima
  • Katsuya Iwata
  • Jun-ichi Yamaguchi
  • Kazuya Maeda
  • Kousei Ito
  • Hiroshi Suzuki
  • Yuichi Sugiyama
  • Hiroyuki KusuharaEmail author
Research Paper

Abstract

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.

KEY WORDS

multidrug and toxin extrusion protein organic cation transporter thiamine vitamin b1 

Abbreviations

AUC

Area under the plasma concentration–time curve

BBM

Brush border membrane

CLplasma

Total body clearance with regard to the plasma concentration

CLR

Renal clearance

GFR

Glomerular filtration rate

LC-MS/MS

Liquid chromatograph-tandem mass spectrometer

MATE

Multidrug and toxin extrusion protein

MEC

Mammary epithelial cells

MPP+

1-methyl-4-phenylpyridinium

OCT

Organic cation transporter

Oct1/2(+/+) mice

Oct1 and Oct2 gene wild-type mice

Oct1/2(−/−) mice

Oct1 and Oct2 gene-knockout mice

Rb

Blood-to-plasma concentration ratio

RFC

Reduced folate carrier

TEA

Tetraethylammonium

THTR

Thiamine transporter

TMP

Thiamine monophosphate

TPK

Thiamine pyrophosphokinase

TPP

Thiamine pyrophosphate

Xurine

Urinary excretion amount

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by a Grant-in-Aid for Scientific Research (S) [Grant 24229002], for Scientific Research (B) [Grant 23390034; 26293032] from the Japan Society for the Promotion of Science, Japan, and from the Scientific Research on Innovative Areas HD-Physiology [Grant 23136101] from the Ministry of Education, Science, and Culture of Japan. We thank T. Yahara, M. Ohmichi, M. Ohkubo and Y. Hasegawa of the Taisho Pharmaceutical Company for their skilled and expert technical assistance. K. Kato, K. Hachiuma, N. Hagima, K. Iwata, and J. Yamaguchi are full-time employees of Taisho Pharmaceutical Company. The authors have no conflicts of interest that are directly relevant to this study.

Supplementary material

11095_2014_1608_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 33 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • 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
    Email author
  1. 1.Drug Safety and Pharmacokinetics LaboratoriesTaisho Pharmaceutical Co. Ltd.SaitamaJapan
  2. 2.Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  3. 3.Department of Pediatrics, The University of Tokyo Hospital Faculty of MedicineThe University of TokyoTokyoJapan
  4. 4.Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical SciencesChiba UniversityChibaJapan
  5. 5.Department of Pharmacy, The University of Tokyo Hospital Faculty of MedicineThe University of TokyoTokyoJapan
  6. 6.Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for InnovationRIKENKanagawaJapan

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