Advertisement

Pharmaceutical Research

, Volume 21, Issue 1, pp 61–67 | Cite as

Expression Levels of Renal Organic Anion Transporters (OATs) and Their Correlation with Anionic Drug Excretion in Patients with Renal Diseases

  • Yuji Sakurai
  • Hideyuki Motohashi
  • Harumasa Ueo
  • Satohiro Masuda
  • Hideyuki Saito
  • Masahiro Okuda
  • Noriko Mori
  • Motokazu Matsuura
  • Toshio Doi
  • Atsushi Fukatsu
  • Osamu Ogawa
  • Ken-ichi Inui
Article

Abstract

Purpose. Because the urinary excretion of drugs is often decreased in renal diseases, dosage regimens are adjusted to avoid adverse drug reactions. The aim of present study was to clarify the alteration in the levels of renal drug transporters and their correlation with the urinary drug excretion in renal diseases patients.

Methods. We quantified the mRNA levels of human organic anion transporters (hOATs) by real-time polymerase chain reaction and examined the excretion of the anionic drug, cefazolin, in renal disease patients. Moreover, transport of cefazolin by hOAT1 and hOAT3 were examined using HEK293 transfectants.

Results. Among four hOATs, the level of hOAT1 mRNA was significantly lower in the kidney of patients with renal diseases than in the normal controls. The elimination constant of cefazolin showed a significant correlation with the values of phenolsulfonphthalein test and mRNA levels of hOAT3. The uptake study using HEK293 transfectants revealed that cefazolin and phenolsulfonphthalein were transported by hOAT3.

Conclusions. These results suggest that hOAT3 plays an important role for anionic drug secretion in patients with renal diseases and that the expression levels of drug transporters may be related to the alteration of renal drug secretion.

organic anion transporter renal diseases human kidney renal tubular secretion real-time PCR 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    L. Dettli. Drug dosage in renal disease. Clin. Pharmacokinet. 1:126-134 (1976).Google Scholar
  2. 2.
    R. Hori, K. Okumura, A. Kamiya, H. Nihira, and H. Nakano. Ampicillin and cephalexin in renal insufficiency. Clin. Pharmacol. Ther. 34:792-798 (1983).Google Scholar
  3. 3.
    R. Hori, K. Okumura, H. Nihira, H. Nakano, K. Akagi, and A. Kamiya. A new dosing regimen in renal insufficiency: application to cephalexin. Clin. Pharmacol. Ther. 38:290-295 (1985).Google Scholar
  4. 4.
    J. V. Moller and M. I. Sheikh. Renal organic anion transport system: pharmacological, physiological, and biochemical aspects. Pharmacol. Rev. 34:315-358 (1982).Google Scholar
  5. 5.
    G. Burckhardt and N. A. Wolff. Structure of renal organic anion and cation transporters. Am. J. Physiol. Renal Physiol. 278:F853-F866 (2000).Google Scholar
  6. 6.
    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
  7. 7.
    T. Sekine, S. H. Cha, and H. Endou. The multispecific organic anion transporter (OAT) family. Pflugers Arch. 440:337-350 (2000).Google Scholar
  8. 8.
    M. Hosoyamada, T. Sekine, Y. Kanai, and H. Endou. Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am. J. Physiol. 276:F122-F128 (1999).Google Scholar
  9. 9.
    R. Lu, B. S. Chan, and V. L. Schuster. Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C. Am. J. Physiol. 276:F295-F303 (1999).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.
    A. Enomoto, M. Takeda, M. Shimoda, S. Narikawa, Y. Kobayashi, T. Yamamoto, T. Sekine, S. H. Cha, T. Niwa, and H. Endou. Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J. Pharmacol. Exp. Ther. 301:797-802 (2002).Google Scholar
  12. 12.
    S. H. Cha, T. Sekine, J. Fukushima, Y. Kanai, Y. Kobayashi, T. Goya, and H. Endou. Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol. Pharmacol. 59:1277-1286 (2001).Google Scholar
  13. 13.
    D. H. Sweet, D. S. Miller, J. B. Pritchard, Y. Fujiwara, D. R. Beier, and S. K. Nigam. Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J. Biol. Chem. 277:26934-26943 (2002).Google Scholar
  14. 14.
    E. Babu, M. Takeda, S. Narikawa, Y. Kobayashi, A. Enomoto, A. Tojo, S. H. Cha, T. Sekine, D. Sakthisekaran, and H. Endou. Role of human organic anion transporter 4 in the transport of ochratoxin A. Biochim. Biophys. Acta 1590:64-75 (2002).Google Scholar
  15. 15.
    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
  16. 16.
    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
  17. 17.
    M. Takeda, S. Narikawa, M. Hosoyamada, S. H. Cha, T. Sekine, and H. Endou. Characterization of organic anion transport inhibitors using cells stably expressing human organic anion transporters. Eur. J. Pharmacol. 419:113-120 (2001).Google Scholar
  18. 18.
    K. Takahashi, S. Masuda, N. Nakamura, H. Saito, T. Futami, T. Doi, and K. Inui. Upregulation of H+-peptide cotransporter PEPT2 in rat remnant kidney. Am. J. Physiol. Renal Physiol. 281:F1109-F1116 (2001).Google Scholar
  19. 19.
    A. Takeuchi, S. Masuda, H. Saito, T. Doi, and K. Inui. Role of kidney-specific organic anion transporters in the urinary excretion of methotrexate. Kidney Int. 60:1058-1068 (2001).Google Scholar
  20. 20.
    L. Ji, S. Masuda, H. Saito, and K. Inui. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int. 62:514-524 (2002).Google Scholar
  21. 21.
    E. K. Brodwall, T. Bergan, and O. Ørjavik. Kidney transport of cefazolin in normal and impaired renal function. J. Antimicrob. Chemother. 3:585-592 (1977).Google Scholar
  22. 22.
    G. R. Brown. Cephalosporin-probenecid drug interactions. Clin. Pharmacokinet. 24:289-300 (1993).Google Scholar
  23. 23.
    M. I. Sheikh. Renal handling of phenol red. I. A comparative study on the accumulation of phenol red and p-aminohippurate in rabbit kidney tubules in vitro. J. Physiol. 227:565-590 (1972).Google Scholar
  24. 24.
    S. Jariyawat, T. Sekine, M. Takeda, N. Apiwattanakul, Y. Kanai, S. Sophasan, and H. Endou. The interaction and transport of β-lactam antibiotics with the cloned rat renal organic anion transporter 1. J. Pharmacol. Exp. Ther. 290:672-677 (1999).Google Scholar
  25. 25.
    K. Y. Jung, M. Takeda, M. Shimoda, S. Narikawa, A. Tojo, K. Kim do, A. Chairoungdua, B. K. Choi, H. Kusuhara, Y. Sugiyama, T. Sekine, and H. Endou. Involvement of rat organic anion transporter 3 (rOAT3) in cephaloridine-induced nephrotoxicity: in comparison with rOAT1. Life Sci. 70:1861-1874 (2002).Google Scholar
  26. 26.
    M. Takeda, E. Babu, S. Narikawa, and H. Endou. Interaction of human organic anion transporters with various cephalosporin antibiotics. Eur. J. Pharmacol. 438:137-142 (2002).Google Scholar
  27. 27.
    Y. Uwai, H. Saito, and K. Inui. Rat renal organic anion transporter rOAT1 mediates transport of urinary-extreted cephalosporins, but not of biliary-extracted cefoperazon. Drug. Metabol. Pharmacokin. 17:125-129 (2002).Google Scholar
  28. 28.
    M. Burg, L. Stoner, J. Cardinal, and N. Green. Furosemide effect on isolated perfused tubules. Am. J. Physiol. 225:119-124 (1973).Google Scholar
  29. 29.
    J. F. Seely and J. H. Dirks. Site of action of diuretic drugs. Kidney Int. 11:1-8 (1977).Google Scholar
  30. 30.
    Y. Uwai, H. Saito, Y. Hashimoto, and K. Inui. Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. J. Pharmacol. Exp. Ther. 295:261-265 (2000).Google Scholar

Copyright information

© Plenum Publishing Corporation 2004

Authors and Affiliations

  • Yuji Sakurai
    • 1
  • Hideyuki Motohashi
    • 1
  • Harumasa Ueo
    • 1
  • Satohiro Masuda
    • 1
  • Hideyuki Saito
    • 1
  • Masahiro Okuda
    • 1
  • Noriko Mori
    • 2
  • Motokazu Matsuura
    • 3
  • Toshio Doi
    • 3
  • Atsushi Fukatsu
    • 4
  • Osamu Ogawa
    • 5
  • Ken-ichi Inui
    • 1
  1. 1.Department of Pharmacy, Kyoto University Hospital, Faculty of MedicineKyoto UniversitySakyo-ku, KyotoJapan
  2. 2.Department of NephrologyShizuoka Prefectural HospitalShizuokaJapan
  3. 3.Department of Clinical Biology and MedicineUniversity of TokushimaTokushimaJapan
  4. 4.Division of Artificial Kidneys, Kyoto University Hospital, Faculty of MedicineKyoto UniversitySakyo-ku, KyotoJapan
  5. 5.Department of Urology, Kyoto University Hospital, Faculty of MedicineKyoto UniversitySakyo-ku, KyotoJapan

Personalised recommendations