Skip to main content
SpringerLink
Log in

Creatinine Transport by Basolateral Organic Cation Transporter hOCT2 in the Human Kidney

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. Creatinine is excreted into urine by tubular secretion in addition to glomerular filtration. The purpose of this study was to clarify molecular mechanisms underlying the tubular secretion of creatinine in the human kidney.

Methods. Transport of [14C]creatinine by human organic ion transporters (SLC22A) was assessed by HEK293 cells expressing hOCT1, hOCT2, hOCT2-A, hOAT1, and hOAT3.

Results. Among the organic ion transporters examined, only hOCT2 stimulated creatinine uptake when expressed in HEK293 cells. Creatinine uptake by hOCT2 was dependent on the membrane potential. The Michaelis constant (Km) for creatinine transport by hOCT2 was 4.0 mM, suggesting low affinity. Various cationic drugs including cimetidine and trimethoprim, but not anionic drugs, markedly inhibited creatinine uptake by hOCT2.

Conclusion. These results suggest that hOCT2, but not hOCT1, is responsible for the basolateral membrane transport of creatinine in the human kidney.

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

Similar content being viewed by others

References

  1. J. B. Pritchard and D. S. Miller. Mechanisms mediating renal secretion of organic anions and cations. Physiol. Rev. 73:765-796 (1993).

    Google Scholar 

  2. K. J. Ullrich. Specificity of transporters for ‘organic anions’ and ‘organic cations’ in the kidney. Biochim. Biophys. Acta 1197:45-62 (1994).

    Google Scholar 

  3. H. Koepsell. Organic cation transporters in intestine, kidney, liver, and brain. Annu. Rev. Physiol. 60:243-266 (1998).

    Google Scholar 

  4. K. Inui and M. Okuda. Cellular and molecular mechanisms of renal tubular secretion of organic anions and cations. Clin. Exp. Nephrol. 2:100-108 (1998).

    Google Scholar 

  5. K. Inui, S. Masuda, and H. Saito. Cellular and molecular aspects of drug transport in the kidney. Kidney Int. 58:944-958 (2000).

    Google Scholar 

  6. 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 

  7. D. Gründemann, V. Gorboulev, S. Gambaryan, M. Veyhl, and H. Koepsell. Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549-552 (1994).

    Google Scholar 

  8. A. E. Busch, S. Quester, J. C. Ulzheimer, V. Gorboulev, A. Akhoundova, S. Waldegger, F. Lang, and H. Koepsell. Monoamine neurotransmitter transport mediated by the polyspecific cation transporter rOCT1. FEBS Lett. 395:153-156 (1996).

    Google Scholar 

  9. A. E. Busch, S. Quester, J. C. Ulzheimer, S. Waldegger, V. Gorboulev, P. Arndt, F. Lang, and H. Koepsell. Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCT1. J. Biol. Chem. 271:32599-32604 (1996).

    Google Scholar 

  10. M. Okuda, Y. Urakami, H. Saito, and K. Inui. Molecular mechanisms of organic cation transport in OCT2-expressing Xenopus oocytes. Biochim. Biophys. Acta 1417:224-231 (1999).

    Google Scholar 

  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. D. Gründemann, G. Liebich, N. Kiefer, S. Koster, and E. Schömig. Selective substrates for non-neuronal monoamine transporters. Mol. Pharmacol. 56:1-10 (1999).

    Google Scholar 

  13. 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 

  14. U. Karbach, J. Kricke, F. Meyer-Wentrup, V. Gorboulev, C. Volk, D. Loffing-Cueni, B. Kaissling, S. Bachmann, and H. Koepsell. Localization of organic cation transporters OCT1 and OCT2 in rat kidney. Am. J. Physiol. 279:F679-F687 (2000).

    Google Scholar 

  15. M. Sugawara-Yokoo, Y. Urakami, H. Koyama, K. Fujikura, S. Masuda, H. Saito, T. Naruse, K. Inui, and K. Takata. Differential localization of organic cation transporters rOCT1 and rOCT2 in the basolateral membrane of rat kidney proximal tubules. Histochem. Cell Biol. 114:175-180 (2000).

    Google Scholar 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. 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).

    Google Scholar 

  21. J. Shannon. The renal excretion of creatinine in man. J. Clin. Invest. 14:403-410 (1935).

    Google Scholar 

  22. B. F. Miller and A. W. Winkler. The renal excretion of endogenous creatinine in man. Comparison with exogenous creatinine and inulin. J. Clin. Invest. 17:31-40 (1938).

    Google Scholar 

  23. G. M. Berlyne, H. Varley, S. Nilwarangkur, and M. Hoerni. Endogenous creatinine clearance and glomerular filtration rate. Lancet 2:874-876 (1964).

    Google Scholar 

  24. B. Hood, P. O. Attman, J. Ahlmen, and R. Jagenburg. Renal hemodynamics and limitations of creatinine clearance in determining filtration rate in glomerular disease. Scand. J. Urol. Nephrol. 5:154-161 (1971).

    Google Scholar 

  25. B. J. Carrie, H. V. Golbetz, A. S. Michaels, and B. D. Myers. Creatinine: an inadequate filtration marker in glomerular diseases. Am. J. Med. 69:177-182 (1980).

    Google Scholar 

  26. J. H. Bauer, C. S. Brooks, and R. N. Burch. Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am. J. Kidney Dis. 2:337-346 (1982).

    Google Scholar 

  27. O. Shemesh, H. Golbetz, J. P. Kriss, and B. D. Myers. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int. 28:830-838 (1985).

    Google Scholar 

  28. F. Berglund, J. Killander, and R. Pompeius. Effect of trimethoprim-sulfamethoxazole on the renal excretion of creatinine in man. J. Urol. 114:802-808 (1975).

    Google Scholar 

  29. E. Burgess, A. Blair, K. Krichman, and R. E. Cutler. Inhibition of renal creatinine secretion by cimetidine in humans. Ren. Physiol. 5:27-30 (1982).

    Google Scholar 

  30. B. A. C. van Acker, G. C. M. Koomen, M. G. Koopman, D. R. de Waart, and L. Arisz. Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate. Lancet 340:1326-1329 (1992).

    Google Scholar 

  31. B. Crawford. Depression of the exogenous creatinine/inulin or thiosulfate clearance ratios in man by diodrast and p-amino-hippuric acid. J. Clin. Invest. 27:171-175 (1948).

    Google Scholar 

  32. H. C. Burry and P. A. Dieppe. Apparent reduction of endogenous creatinine clearance by salicylate treatment. BMJ 2:16-17 (1976).

    Google Scholar 

  33. W. M. Barendt and S. H. Wright. The human organic cation transporter (hOCT2) recognizes the degree of substrate ionization. J. Biol. Chem. 277:22491-22496 (2002).

    Google Scholar 

  34. J. G. van den Berg, M. G. Koopman, and L. Arisz. Ranitidine has no influence on tubular creatinine secretion. Nephron 74:705-708 (1996).

    Google Scholar 

  35. J. H. Lin. Pharmacokinetic and pharmacodynamic properties of histamine H2-receptor antagonists. Relationship between intrinsic potency and effective plasma concentrations. Clin. Pharmacokinet. 20:218-236 (1991).

    Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Yumiko Urakami, Naoko Kimura, Masahiro Okuda & Ken-ichi Inui

Authors
  1. Yumiko Urakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoko Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masahiro Okuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ken-ichi Inui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ken-ichi Inui.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Urakami, Y., Kimura, N., Okuda, M. et al. Creatinine Transport by Basolateral Organic Cation Transporter hOCT2 in the Human Kidney. Pharm Res 21, 976–981 (2004). https://doi.org/10.1023/B:PHAM.0000029286.45788.ad

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:PHAM.0000029286.45788.ad

Search

Navigation