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 [(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.
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 [(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: Wolfgang Stuetz; Verena Ilona Carrara; Rose McGready; Sue Jean Lee; Hans Konrad Biesalski; François Henry Nosten Journal: PLoS One Date: 2012-06-29 Impact factor: 3.240
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