Skip to main content

Advertisement

SpringerLink
Log in

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

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

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

References

  1. Nies AT, Koepsell H, Damme K, Schwab M. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol. 2011;201:105–67.

    Article  CAS  PubMed  Google Scholar 

  2. Jonker JW, Schinkel AH. Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther. 2004;308(1):2–9.

    Article  CAS  PubMed  Google Scholar 

  3. Bleasby K, Castle JC, Roberts CJ, Cheng C, Bailey WJ, Sina JF, et al. Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition. Xenobiotica. 2006;36(10–11):963–88.

    Article  CAS  PubMed  Google Scholar 

  4. Yonezawa A, Inui K. Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J Pharmacol. 2011;164(7):1817–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kato K, Mori H, Kito T, Yokochi M, Ito S, Inoue K, et al. Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins. Pharm Res. 2014;31(1):136–47.

    Article  CAS  PubMed  Google Scholar 

  6. Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007;74(2):359–71.

    Article  CAS  PubMed  Google Scholar 

  7. Bettendorff L, Wins P. Thiamin diphosphate in biological chemistry: new aspects of thiamin metabolism, especially triphosphate derivatives acting other than as cofactors. FEBS J. 2009;276(11):2917–25.

    Article  CAS  PubMed  Google Scholar 

  8. Zastre JA, Sweet RL, Hanberry BS, Ye S. Linking vitamin B1 with cancer cell metabolism. Cancer Metab. 2013;1(1):16.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Foulon V, Antonenkov VD, Croes K, Waelkens E, Mannaerts GP, Van Veldhoven PP, et al. Purification, molecular cloning, and expression of 2-hydroxyphytanoyl-CoA lyase, a peroxisomal thiamine pyrophosphate-dependent enzyme that catalyzes the carbon-carbon bond cleavage during alpha-oxidation of 3-methyl-branched fatty acids. Proc Natl Acad Sci U S A. 1999;96(18):10039–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wolfe SJ, Brin M, Davidson CS. The effect of thiamine deficiency on human erythrocyte metabolism. J Clin Invest. 1958;37(11):1476–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Krishna S, Taylor AM, Supanaranond W, Pukrittayakamee S, ter Kuile F, Tawfiq KM, et al. Thiamine deficiency and malaria in adults from southeast Asia. Lancet. 1999;353(9152):546–9.

    Article  CAS  PubMed  Google Scholar 

  12. Thornalley PJ, Babaei-Jadidi R, Al Ali H, Rabbani N, Antonysunil A, Larkin J, et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia. 2007;50(10):2164–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rabbani N, Alam SS, Riaz S, Larkin JR, Akhtar MW, Shafi T, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia. 2009;52(2):208–12.

    Article  CAS  PubMed  Google Scholar 

  14. Dutta B, Huang W, Molero M, Kekuda R, Leibach FH, Devoe LD, et al. Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem. 1999;274(45):31925–9.

    Article  CAS  PubMed  Google Scholar 

  15. Said HM, Balamurugan K, Subramanian VS, Marchant JS. Expression and functional contribution of hTHTR-2 in thiamin absorption in human intestine. Am J Physiol Gastrointest Liver Physiol. 2004;286(3):G491–8.

    Article  CAS  PubMed  Google Scholar 

  16. Zhao R, Goldman ID. Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors. Mol Aspects Med. 2013;4(2–3):373–85.

    Article  Google Scholar 

  17. Larkin JR, Zhang F, Godfrey L, Molostvov G, Zehnder D, Rabbani N, et al. Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes. PLoS One. 2012;7(12):e53175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Spector R, Johanson CE. Vitamin transport and homeostasis in mammalian brain: focus on Vitamins B and E. J Neurochem. 2007;103(2):425–38.

    Article  CAS  PubMed  Google Scholar 

  19. Diaz GA, Banikazemi M, Oishi K, Desnick RJ, Gelb BD. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Nat Genet. 1999;22(3):309–12.

    Article  CAS  PubMed  Google Scholar 

  20. Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet. 1999;22(3):305–8.

    Article  CAS  PubMed  Google Scholar 

  21. Oishi K, Hofmann S, Diaz GA, Brown T, Manwani D, Ng L, et al. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Hum Mol Genet. 2002;11(23):2951–60.

    Article  CAS  PubMed  Google Scholar 

  22. Zeng WQ, Al-Yamani E, Acierno Jr JS, Slaugenhaupt S, Gillis T, MacDonald ME, et al. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet. 2005;77(1):16–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reidling JC, Lambrecht N, Kassir M, Said HM. Impaired intestinal vitamin B1 (thiamin) uptake in thiamin transporter-2-deficient mice. Gastroenterology. 2010;138(5):1802–9.

    Article  CAS  PubMed  Google Scholar 

  24. Yoshioka K. Some properties of the thiamine uptake system in isolated rat hepatocytes. Biochim Biophys Acta. 1984;778(1):201–9.

    Article  CAS  PubMed  Google Scholar 

  25. Weber W, Nitz M, Looby M. Nonlinear kinetics of the thiamine cation in humans: saturation of nonrenal clearance and tubular reabsorption. J Pharmacokinet Biopharm. 1990;18(6):501–23.

    Article  CAS  PubMed  Google Scholar 

  26. Shamir R. Thiamine-deficient infant formula: what happened and what have we learned? Ann Nutr Metab. 2012;60(3):185–7.

    Article  CAS  PubMed  Google Scholar 

  27. Ito N, Ito K, Ikebuchi Y, Kito T, Miyata H, Toyoda YM, et al. Organic cation transporter/solute carrier family 22a is involved in drug transfer into milk in mice. J Pharm Sci. 2014;103(10):3342–8.

    Article  CAS  PubMed  Google Scholar 

  28. Ito S, Kusuhara H, Kuroiwa Y, Wu C, Moriyama Y, Inoue K, et al. Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine. J Pharmacol Exp Ther. 2010;333(1):341–50.

    Article  CAS  PubMed  Google Scholar 

  29. Hirano M, Maeda K, Shitara Y, Sugiyama Y. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther. 2004;311(1):139–46.

    Article  CAS  PubMed  Google Scholar 

  30. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75.

    CAS  PubMed  Google Scholar 

  31. Yamaoka K, Tanigawara Y, Nakagawa T, Uno T. A pharmacokinetic analysis program (multi) for microcomputer. J Pharmacobiodyn. 1981;4(11):879–85.

    Article  CAS  PubMed  Google Scholar 

  32. Yamazaki M, Suzuki H, Hanano M, Tokui T, Komai T, Sugiyama Y. Na(+)-independent multispecific anion transporter mediates active transport of pravastatin into rat liver. Am J Physiol. 1993;264(1 Pt 1):G36–44.

    CAS  PubMed  Google Scholar 

  33. Jonker JW, Wagenaar E, Van Eijl S, Schinkel AH. Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol. 2003;23(21):7902–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Higgins JW, Bedwell DW, Zamek-Gliszczynski MJ. Ablation of both organic cation transporter (OCT)1 and OCT2 alters metformin pharmacokinetics but has no effect on tissue drug exposure and pharmacodynamics. Drug Metab Dispos. 2012;40(6):1170–7.

    Article  CAS  PubMed  Google Scholar 

  35. Ito N, Ito K, Koshimichi H, Hisaka A, Honma M, Igarashi T, et al. Contribution of protein binding, lipid partitioning, and asymmetrical transport to drug transfer into milk in mouse versus human. Pharm Res. 2013;30(9):2410–22.

    Article  CAS  PubMed  Google Scholar 

  36. Wielders JP, Mink CJ. Quantitative analysis of total thiamine in human blood, milk and cerebrospinal fluid by reversed-phase ion-pair high-performance liquid chromatography. J Chromatogr. 1983;277:145–56.

    Article  CAS  PubMed  Google Scholar 

  37. Rindi G, De Giuseppe L, Sciorelli G. Thiamine monophosphate, a normal constituent of rat plasma. J Nutr. 1968;94(4):447–54.

    CAS  PubMed  Google Scholar 

  38. Boulware MJ, Subramanian VS, Said HM, Marchant JS. Polarized expression of members of the solute carrier SLC19A gene family of water-soluble multivitamin transporters: implications for physiological function. Biochem J. 2003;376(Pt 1):43–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10(7):1093–5.

    Article  CAS  PubMed  Google Scholar 

  40. Makarchikov AF, Wins P, Janssen E, Wieringa B, Grisar T, Bettendorff L. Adenylate kinase 1 knockout mice have normal thiamine triphosphate levels. Biochim Biophys Acta. 2002;1592(2):117–21.

    Article  CAS  PubMed  Google Scholar 

  41. Ferrebee JW, Weissman N, Parker D, Owen PS. Tissue thiamin concentrations and urinary thiamin excretion. J Clin Invest. 1942;21(4):401–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302(2):510–5.

    Article  CAS  PubMed  Google Scholar 

  43. Zhao R, Gao F, Goldman ID. Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells. Am J Physiol Cell Physiol. 2002;282(6):C1512–7.

    Article  CAS  PubMed  Google Scholar 

  44. Rindi G, Laforenza U. Thiamine intestinal transport and related issues: recent aspects. Proc Soc Exp Biol Med. 2000;224(4):246–55.

    Article  CAS  PubMed  Google Scholar 

  45. Han TK, Everett RS, Proctor WR, Ng CM, Costales CL, Brouwer KL, et al. Organic cation transporter 1 (OCT1/mOct1) is localized in the apical membrane of Caco-2 cell monolayers and enterocytes. Mol Pharmacol. 2013;84(2):182–9.

    Article  CAS  PubMed  Google Scholar 

  46. Lockman PR, Mumper RJ, Allen DD. Evaluation of blood–brain barrier thiamine efflux using the in situ rat brain perfusion method. J Neurochem. 2003;86(3):627–34.

    Article  CAS  PubMed  Google Scholar 

  47. van Herwaarden AE, Wagenaar E, Merino G, Jonker JW, Rosing H, Beijnen JH, et al. Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol. 2007;27(4):1247–53.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Stuetz W, Carrara VI, McGready R, Lee SJ, Biesalski HK, Nosten FH. Thiamine diphosphate in whole blood, thiamine and thiamine monophosphate in breast-milk in a refugee population. PLoS One. 2012;7(6):e36280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Takeuchi A, Motohashi H, Okuda M, Inui K. Decreased function of genetic variants, Pro283Leu and Arg287Gly, in human organic cation transporter hOCT1. Drug Metab Pharmacokinet. 2003;18(6):409–12.

    Article  CAS  PubMed  Google Scholar 

  50. Choi MK, Song IS. Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm Drug Dispos. 2012;33(3):170–8.

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan

    Koji Kato, Kenji Hachiuma, Naoko Hagima, Katsuya Iwata & Jun-ichi Yamaguchi

  2. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo Bunkyo-ku, Tokyo, 113-0033, Japan

    Chihiro Moriyama, Xuan Zhang, Kazuya Maeda & Hiroyuki Kusuhara

  3. Department of Pediatrics, The University of Tokyo Hospital Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Naoki Ito

  4. Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan

    Kousei Ito

  5. Department of Pharmacy, The University of Tokyo Hospital Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Hiroshi Suzuki

  6. Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan

    Yuichi Sugiyama

Authors
  1. Koji Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chihiro Moriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenji Hachiuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoko Hagima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katsuya Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jun-ichi Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kazuya Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kousei Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroshi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yuichi Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hiroyuki Kusuhara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroyuki Kusuhara.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 33 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kato, K., Moriyama, C., Ito, N. et al. Involvement of Organic Cation Transporters in the Clearance and Milk Secretion of Thiamine in Mice. Pharm Res 32, 2192–2204 (2015). https://doi.org/10.1007/s11095-014-1608-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1608-8

KEY WORDS

Search

Navigation