Skip to main content
Log in

Renal Transport of Adefovir, Cidofovir, and Tenofovir by SLC22A Family Members (hOAT1, hOAT3, and hOCT2)

  • Short Communication
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The nephrotoxicity of the nucleotide antivirals adefovir, cidofovir and tenofovir is considered to depend on the renal tubular transport of them. Although it is known that the antivirals are substrates of the human renal organic anion transporter hOAT1 (SLC22A6), there is no information available on other organic ion transporters. The aim of the present study was to investigate whether the other renal organic anion transporter hOAT3 (SLC22A8) and organic cation transporter hOCT2 (SLC22A2) transport the antivirals.

Materials and Methods

Uptake experiments were performed using HEK293 cells transfected with cDNA of the organic ion transporters.

Results

The uptake of adefovir, cidofovir and tenofovir in monolayers stably expressing hOAT3 increased time-dependently, compared with control. Probenecid, a typical inhibitor of organic anion transporters, completely inhibited their transport. The amounts of the antivirals taken up by hOAT3 were much lower than those by hOAT1. The transient expression of hOCT2 did not increase uptake of the antivirals.

Conclusion

These results indicate that adefovir, cidofovir and tenofovir are substrates of hOAT3 as well as hOAT1, but that quantitatively hOAT1 is the major renal transporter for these drugs.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Abbreviations

hOAT:

human organic anion transporter

hOCT:

human organic cation transporter

MRP:

multidrug resistance protein.

References

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

    Article  PubMed  CAS  Google Scholar 

  2. H. Koepsell and H. Endou. The SLC22 drug transporter family. Pflugers Arch. 447:666–676 (2004).

    Article  PubMed  CAS  Google Scholar 

  3. J. W. Jonker and A. H. Schinkel. Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1–3). J. Pharmacol. Exp. Ther. 308:2–9 (2004).

    Article  PubMed  CAS  Google Scholar 

  4. H. Miyazaki, T. Sekine, and H. Endou. The multispecific organic anion transporter family: properties and pharmacological significance. Trends Pharmacol. Sci. 25:654–662 (2004).

    Article  PubMed  CAS  Google Scholar 

  5. 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).

    PubMed  CAS  Google Scholar 

  6. D. H. Sweet. Organic anion transporter (Slc22a) family members as mediators of toxicity. Toxicol. Appl. Pharmacol. 204:198–215 (2005).

    Article  PubMed  CAS  Google Scholar 

  7. A. Yonezawa, S. Masuda, K. Nishihara, I. Yano, T. Katsura, and K. Inui. Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat. Biochem. Pharmacol. 70:1823–1831 (2005).

    Article  PubMed  CAS  Google Scholar 

  8. H. Izzedine, V. Launay-Vacher, and G. Deray. Antiviral drug-induced nephrotoxicity. Am. J. Kidney. Dis. 45:804–817 (2005).

    Article  PubMed  CAS  Google Scholar 

  9. T. Cihlar, E. S. Ho, D. C. Lin, and A. S. Mulato. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids 20:641–648 (2001).

    Article  PubMed  CAS  Google Scholar 

  10. E. S. Ho, D. C. Lin, D. B. Mendel, and T. Cihlar. Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J. Am. Soc. Nephrol. 11:383–393 (2000).

    PubMed  CAS  Google Scholar 

  11. Y. Sakurai, H. Motohashi, H. Ueo, S. Masuda, H. Saito, M. Okuda, N. Mori, M. Matsuura, T. Doi, A. Fukatsu, O. Ogawa, and K. Inui. Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases. Pharm. Res. 21:61–67 (2004).

    Article  PubMed  CAS  Google Scholar 

  12. Y. Sakurai, H. Motohashi, K. Ogasawara, T. Terada, S. Masuda, T. Katsura, N. Mori, M. Matsuura, T. Doi, A. Fukatsu, and K. Inui. Pharmacokinetic significance of renal OAT3 (SLC22A8) for anionic drug elimination in patients with mesangial proliferative glomerulonephritis. Pharm. Res. 22:2016–2022 (2005).

    Article  PubMed  CAS  Google Scholar 

  13. H. Ueo, H. Motohashi, T. Katsura, and K. Inui. Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem. Pharmacol. 70:1104–1113 (2005).

    Article  PubMed  CAS  Google Scholar 

  14. 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).

    Article  PubMed  CAS  Google Scholar 

  15. J. D. Schuetz, M. C. Connelly, D. Sun, S. G. Paibir, P. M. Flynn, R. V. Srinivas, A. Kumar, and A. Fridland. MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat. Med. 5:1048–1051 (1999).

    Article  PubMed  CAS  Google Scholar 

  16. S. Dallas, L. Schlichter, and R. Bendayan. Multidrug resistance protein (MRP) 4- and MRP 5-mediated efflux of 9-(2-phosphonylmethoxyethyl)adenine by microglia. J. Pharmacol. Exp. Ther. 309:1221–1229 (2004).

    Article  PubMed  CAS  Google Scholar 

  17. M. Leggas, M. Adachi, G. L. Scheffer, D. Sun, P. Wielinga, G. Du, K. E. Mercer, Y. Zhuang, J. C. Panetta, B. Johnston, R. J. Scheper, C. F. Stewart, and J. D. Schuetz. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol. Cell. Biol. 24:7612–7621 (2004).

    Article  PubMed  CAS  Google Scholar 

  18. H. Motohashi, Y. Uwai, K. Hiramoto, M. Okuda, and K. Inui. Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A). Eur. J. Pharmacol. 503:25–30 (2004).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a grant-in-aid for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan, by a Japan Health Science Foundation “Research on Health Sciences Focusing on Drug Innovation,” by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Culture and Sports of Japan, and by the 21st Century COE program “Knowledge Information Infrastructure for Genome Science.”

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ken-ichi Inui.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Uwai, Y., Ida, H., Tsuji, Y. et al. Renal Transport of Adefovir, Cidofovir, and Tenofovir by SLC22A Family Members (hOAT1, hOAT3, and hOCT2). Pharm Res 24, 811–815 (2007). https://doi.org/10.1007/s11095-006-9196-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-9196-x

Key words

Navigation