title: Involvement of organic cation transporters in the clearance and milk secretion of thiamine in mice.
abstract: OBJECTIVE
  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 [(3)H]thiamine was determined in Oct1-, Oct2-, and Oct3-expressing HEK293 cells and freshly isolated hepatocytes. A pharmacokinetic study of thiamine-d3 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 [(3)H]thiamine by hepatocytes in vitro, and elevated the plasma thiamine concentration by 5.8-fold in vivo. The plasma clearance of thiamine-d3 was significantly decreased in Oct1/2(-/-) mice. At the higher infusion rate of 100 nmol/min/kg thiamine-d3, Oct1/2 defect or pyrimethamine-treatment caused a significant reduction in the renal clearance of thiamine-d3. The total thiamine and thiamine-d3 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.
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.forename: Chihiro
authors.initials: C
authors.lastname: Moriyama
authors.forename: Naoki
authors.initials: N
authors.lastname: Ito
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Kenji
authors.initials: K
authors.lastname: Hachiuma
authors.forename: Naoko
authors.initials: N
authors.lastname: Hagima
authors.forename: Katsuya
authors.initials: K
authors.lastname: Iwata
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Yamaguchi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Kousei
authors.initials: K
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
mesh_terms: D000818:Animals; D001692:Biological Transport; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002853:Chromatography, Liquid; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007774:Lactation; D008297:Male; D008657:Metabolic Clearance Rate; D018345:Mice, Knockout; D008892:Milk / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D013831:Thiamine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D050482:Catecholamine Plasma Membrane Transport Proteins; C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; C103766:Slc22a1 protein, mouse; D013831:Thiamine