Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Antiviral Transport

  1. Michio Takeda1,
  2. Suparat Khamdang1,
  3. Shinichi Narikawa1,
  4. Hiroaki Kimura1,
  5. Yasuna Kobayashi2,
  6. Toshinori Yamamoto2,
  7. Seok Ho Cha1,
  8. Takashi Sekine1 and
  9. Hitoshi Endou1
  1. 1Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan (M.T., S.K., S.N., H.K., S.H.C., T.S., H.E.); and 2Department of Clinical Pharmacy, Showa University School of Pharmaceutical Sciences, Tokyo, Japan (Y.K., T.Y.)
  1. Dr. Hitoshi Endou, Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181, Japan. E-mail:endouh{at}kyorin-u.ac.jp

Abstract

Renal excretion is an important elimination pathway for antiviral agents, such as acyclovir (ACV), ganciclovir (GCV), and zidovudine (AZT). The purpose of this study was to elucidate the molecular mechanisms of renal ACV, GCV, and AZT transport using cells stably expressing human organic anion transporter 1 (hOAT1), hOAT2, hOAT3, and hOAT4, and human organic cation transporter 1 (hOCT1) and hOCT2. Time- and concentration-dependent uptake of ACV and GCV was observed in hOAT1- and hOCT1-expressing cells. In contrast, uptake of valacyclovir,l-valyl ester of ACV, was observed only in hOAT3-expressing cells. On the other hand, AZT uptake was observed in hOAT1-, hOAT2-, hOAT3-, and hOAT4-expressing cells. The Kmvalues of ACV uptake by hOAT1 and hOCT1 were 342.3 and 151.2 μM, respectively, whereas those of GCV uptake by hOAT1 and hOCT1 were 895.5 and 516.2 μM, respectively. On the other hand, theKm values of AZT uptake by hOAT1, hOAT2, hOAT3, and hOAT4 were 45.9, 26.8, 145.1, and 151.8 μM, respectively. In addition, probenecid weakly inhibited the hOAT1-mediated ACV uptake. In conclusion, these results suggest that hOAT1 and hOCT1 mediate renal ACV and GCV transport, whereas hOAT1, hOAT2, hOAT3, and hOAT4 mediate renal AZT transport. In addition, l-valyl ester appears to be important in differential substrate recognition between hOAT1 and hOAT3. hOAT1 may not be the molecule responsible for the drug interaction between ACV and probenecid.

Footnotes

  • This study was supported in part by Grants-in-Aid 11671048, 11694310, and 13671128 from the Ministry of Education, Culture, Sports, Sciences and Technology, the Science Research Promotion Fund of the Japan Private School Promotion Foundation, and Research on Health Sciences focusing on Drug Innovation from Japan Health Sciences Foundation.

  • Abbreviations:
    ACV
    acyclovir
    hOAT
    human organic anion transporter
    hOCT
    human organic cation transporter
    GCV
    ganciclovir
    VACV
    valacyclovir
    AZT
    zidovudine
    S1
    S2, and S3, the first, second, and third segment of proximal tubule
    TEA
    tetraethylammonium
    D-PBS
    Dulbecco's modified phosphate-buffered saline
    PGF2α
    prostaglandin F2α
    PAH
    para-aminohippuric acid
    HIV
    human immunodeficiency virus
    • Received August 28, 2001.
    • Accepted November 11, 2001.
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  1. doi: 10.1124/jpet.300.3.918 JPET March 1, 2002 vol. 300 no. 3 918-924
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