Involvement of Organic Cation Transporters in the Clearance and Milk Secretion of Thiamine in Mice
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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 [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.
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.
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 WORDSmultidrug and toxin extrusion protein organic cation transporter thiamine vitamin b1
Area under the plasma concentration–time curve
Brush border membrane
Total body clearance with regard to the plasma concentration
Glomerular filtration rate
Liquid chromatograph-tandem mass spectrometer
Multidrug and toxin extrusion protein
Mammary epithelial cells
Organic cation transporter
- Oct1/2(+/+) mice
Oct1 and Oct2 gene wild-type mice
- Oct1/2(−/−) mice
Oct1 and Oct2 gene-knockout mice
Blood-to-plasma concentration ratio
Reduced folate carrier
Urinary excretion amount
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.
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