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Metformin Transport by Renal Basolateral Organic Cation Transporter hOCT2

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Purpose.

Metformin, an antihyperglycemic agent, is eliminated by tubular secretion in addition to glomerular filtration in the human kidney. This study was performed to characterize metformin transport by human organic cation transporter 2 (hOCT2), the most abundant organic cation transporter in the basolateral membranes of the human kidney.

Methods.

Accumulation of [14C]metformin was assessed by the tracer experiments in the human embryonic kidney (HEK293) cells expressing hOCT2.

Results.

The transport of [14C]metformin was markedly stimulated in hOCT2-expressing cells compared with the vector-transfected cells. The accumulation of [14C]metformin was concentrative and was dependent on the membrane potential, showing consistency with the characteristics of hOCT2. The apparent Km and Vmax values of [14C]metformin transport by hOCT2-expressing HEK293 cells were 1.38 ± 0.21 mM and 11.9 ± 1.5 nmol mg protein−1 min−1, respectively. The order of the potencies of unlabeled biguanides to inhibit [14C]metformin transport by hOCT2 was phenformin > buformin > metformin. Furthermore, [14C]metformin transport was inhibited slightly or moderately by cationic drugs such as procainamide and quinidine at respective therapeutic concentrations.

Conclusions.

Metformin is transported by the basolateral organic cation transporter hOCT2 in the human kidney. hOCT2 could play a role in the drug interactions between metformin and some cationic drugs.

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Abbreviations

hOCT1:

human organic cation transporter 1

hOCT2:

human organic cation transporter 2

rOCT1:

rat organic cation transporter 1

HEPES:

N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid

References

  1. 1. P. Marchetti, R. Giannarelli, A. di Carlo, and R. Navalesi. Pharmacokinetic optimisation of oral hypoglycaemic therapy. Clin. Pharmacokinet. 21:308–317 (1991).

    Google Scholar 

  2. 2. T. B. Klepser and M. W. Kelly. Metformin hydrochloride: An antihyperglycemic agent. Am. J. Health Syst. Pharm. 54:893–903 (1997).

    Google Scholar 

  3. 3. I. W. Campbell. Metformin and the sulphonylureas: The comparative risk. Horm. Metab. Res. Suppl. 15:105–111 (1985).

    Google Scholar 

  4. 4. C. R. Sirtori, G. Franceschini, M. Galli-Kienle, G. Cighetti, G. Galli, A. Bondioli, and F. Conti. Disposition of metformin (N,N-dimethylbiguanide) in man. Clin. Pharmacol. Ther. 24:683–693 (1978).

    Google Scholar 

  5. 5. P. J. Pentika;auinen, P. J. Neuvonen, and A. Penttila;au. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur. J. Clin. Pharmacol. 16:195–202 (1979).

    Google Scholar 

  6. 6. A. Somogyi and M. Muirhead. Pharmacokinetic interactions of cimetidine 1987. Clin. Pharmacokinet. 12:321–366 (1987).

    Google Scholar 

  7. 7. A. Somogyi, C. Stockley, J. Keal, P. Rolan, and F. Bochner. Reduction of metformin renal tubular secretion by cimetidine in man. Br. J. Clin. Pharmacol. 23:545–551 (1987).

    Google Scholar 

  8. 8. V. Gorboulev, J. C. Ulzheimer, A. Akhoundova, I. Ulzheimer-Teuber, U. Karbach, S. Quester, C. Baumann, F. Lang, A. E. Busch, and H. Koepsell. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 16:871–881 (1997).

    Google Scholar 

  9. 9. L. Zhang, M. J. Dresser, A. T. Gray, S. C. Yost, S. Terashita, and K. M. Giacomini. Cloning and functional expression of a human liver organic cation transporter. Mol. Pharmacol. 51:913–921 (1997).

    Google Scholar 

  10. 10. H. Motohashi, Y. Sakurai, H. Saito, S. Masuda, Y. Urakami, M. Goto, A. Fukatsu, O. Ogawa, and K. Inui. Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J. Am. Soc. Nephrol. 13:866–874 (2002).

    Google Scholar 

  11. 11. Y. Urakami, M. Okuda, S. Masuda, H. Saito, and K. Inui. Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J. Pharmacol. Exp. Ther. 287:800–805 (1998).

    Google Scholar 

  12. 12. Y. Urakami, M. Okuda, S. Masuda, M. Akazawa, H. Saito, and K. Inui. Distinct characteristics of organic cation transporters, OCT1 and OCT2, in the basolateral membrane of renal tubules. Pharm. Res. 18:1528–1534 (2001).

    Google Scholar 

  13. 13. Y. Urakami, M. Akazawa, H. Saito, M. Okuda, and K. Inui. cDNA cloning, functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney. J. Am. Soc. Nephrol. 13:1703–1710 (2002).

    Google Scholar 

  14. 14. D. S. Wang, J. W. Jonker, Y. Kato, H. Kusuhara, A. H. Schinkel, and Y. Sugiyama. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther. 302:510–515 (2002).

    Google Scholar 

  15. 15. D. S. Wang, H. Kusuhara, Y. Kato, J. W. Jonker, A. H. Schinkel, and Y. Sugiyama. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol. Pharmacol. 63:844–848 (2003).

    Google Scholar 

  16. 16. M. J. Dresser, G. Xiao, M. K. Leabman, A. T. Gray, and K. M. Giacomini. Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2). Pharm. Res. 19:1244–1247 (2002).

    Google Scholar 

  17. 17. Y. Urakami, N. Kimura, M. Okuda, and K. Inui. Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney. Pharm. Res. 21:976–981 (2004).

    Google Scholar 

  18. 18. M. M. Bradford. A Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:248–254 (1976).

    Article  CAS  PubMed  Google Scholar 

  19. 19. M. Okuda, H. Saito, Y. Urakami, M. Takano, and K. Inui. cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem. Biophys. Res. Commun. 224:500–507 (1996).

    Google Scholar 

  20. 20. N. C. Sambol, J. Chiang, M. O’Conner, C. Y. Liu, E. T. Lin, A. M. Goodman, L. Z. Benet, and J. H. Karam. Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus. J. Clin. Pharmacol. 36:1012–1021 (1996).

    Google Scholar 

  21. 21. A. J. Scheen. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 30:359–371 (1996).

    Google Scholar 

  22. 22. M. B. Davidson and A. L. Peters. An overview of metformin in the treatment of type 2 diabetes mellitus. Am. J. Med. 102:99–110 (1997).

    Google Scholar 

  23. 23. N. C. Sambol, J. Chiang, E. T. Lin, A. M. Goodman, C. Y. Liu, L. Z. Benet, and M. G. Cogan. Kidney function and age are both predictors of pharmacokinetics of metformin. J. Clin. Pharmacol. 35:1094–1102 (1995).

    Google Scholar 

  24. 24. T. Katsura, M. Takano, Y. Tomita, M. Yasuhara, K. Inui, and R. Hori. Characteristics of organic cation transporter in rat renal basolateral membrane. Biochim. Biophys. Acta 1146:197–202 (1993).

    Google Scholar 

  25. 25. A. Somogyi, A. McLean, and B. Heinzow. Cimetidine-procainamide pharmacokinetic interaction in man: Evidence of competition for tubular secretion of basic drugs. Eur. J. Clin. Pharmacol. 25:339–345 (1983).

    Google Scholar 

  26. 26. R. Larsson, G. Bodemar, and B. Norlander. Oral absorption of cimetidine and its clearance in patients with renal failure. Eur. J. Clin. Pharmacol. 15:153–157 (1979).

    Google Scholar 

  27. 27. P. A. Bjaeldager, J. B. Jensen, N. E. Larsen, and E. F. Hvidberg. Elimination of oral cimetidine in chronic renal failure and during haemodialysis. Br. J. Clin. Pharmacol. 9:585–592 (1980).

    Google Scholar 

  28. 28. A. Somogyi, H. G. Rohner, and R. Gugler. Pharmacokinetics and bioavailability of cimetidine in gastric and duodenal ulcer patients. Clin. Pharmacokinet. 5:84–94 (1980).

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, Kyoto University Hospital, Kyoto University, Kyoto, 606-8507, Japan

    Naoko Kimura, Masahiro Okuda & Ken-ichi Inui

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  1. Naoko Kimura
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  2. Masahiro Okuda
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  3. Ken-ichi Inui
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Correspondence to Ken-ichi Inui.

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Kimura, N., Okuda, M. & Inui, Ki. Metformin Transport by Renal Basolateral Organic Cation Transporter hOCT2. Pharm Res 22, 255–259 (2005). https://doi.org/10.1007/s11095-004-1193-3

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  • DOI: https://doi.org/10.1007/s11095-004-1193-3

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