期刊
PHARMACEUTICAL RESEARCH
卷 32, 期 7, 页码 2192-2204出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-014-1608-8
关键词
multidrug and toxin extrusion protein; organic cation transporter; thiamine; vitamin b1
资金
- Japan Society for the Promotion of Science, Japan [24229002, 23390034, 26293032]
- Ministry of Education, Science, and Culture of Japan [23136101]
- Grants-in-Aid for Scientific Research [23136101, 26293032] Funding Source: KAKEN
To investigate the role of organic cation transporters (Octs) and multidrug and toxin extrusion protein 1 (Mate1) in the disposition of thiamine. The uptake of [H-3]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. Thiamine is a substrate of Oct1 and Oct2, but not Oct3. Oct1/2 defect caused a significant reduction in the uptake of [H-3]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. 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.
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