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Pharmacokinetic Study of the Hepatobiliary Transport of Indomethacin

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Abstract

Purpose. The biliary excreted amount of indomethacin and itsglucuronide is related to the intestinal toxicity of this drug. In the presentstudy, we investigated the hepatobiliary transport of indomethacin.Methods. The uptake of indomethacin into primary cultured rathepatocytes and COS-7 cells transfected with cDNA encoding sodiumtauro-cholate co-transporting polypeptide or organic anion transportingpolypeptide 1 was examined. Moreover, we compared the biliaryexcretion of indomethacin and its glucuronide between Sprague-Dawley(SD) rats and Eisai hyperbilirubinemic rats (EHBR) whose canalicularmultispecific organic anion transporter/multidrug resistance associatedprotein 2 (cMOAT/MRP2) function is hereditarily defective.Results. The uptake of indomethacin into rat hepatocytes was mediatedby Na+-dependent and independent active transport systems. Neithertransfectant stimulated the uptake of indomethacin. After intravenousinfusion of indomethacin to SD rats, the biliary excretion ofindomethacin glucuronide exceeded that of indomethacin. The indomethacintransport clearance across the bile canalicular membrane wascomparable between SD rats and EHBR, whereas the corresponding value forindomethacin glucuronide in EHBR was approximately 50% that inSD rats.Conclusions. These results indicate that another transporter(s) isinvolved in the hepatic uptake of indomethacin and the canaliculartransport of indomethacin glucuronide is mediated by cMOAT/MRP2whereas that of indomethacin is not mediated by cMOAT/MRP2.

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REFERENCES

  1. H. B. Hucker, A. G. Zacchei, S. V. Cox, D. A. Brodie, and N. H. R. Cantwell. Studies on the absorption, distribution and excretion of indomethacin in various species. J. Pharmacol. Exp. Ther. 153:237–249 (1966).

    Google Scholar 

  2. G. Alvan, M. Orme, L. Bertilsson, R. Ekstrand, and L. Palmer. Pharmacokinetics of indomethacin. Clin. Pharmacol. Ther. 18:364–373 (1975).

    Google Scholar 

  3. R. K. Verbeeck, J. L. Blackburn, and G. R. Loewen. Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs. Clin. Pharmacokinetics 8:297–331 (1983).

    Google Scholar 

  4. D. E. Duggan, K. F. Hooke, R. M. Noll, and K. C. Kwan. Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem. Pharmacol. 25:1749–1754 (1975).

    Google Scholar 

  5. P. J. Meier. Molecular mechanisms of hepatic bile salt transport from sinusoidal blood into bile. Am. J. Physiol. 269:G801–G812 (1995).

    Google Scholar 

  6. B. Noe, B. Hagenbuch, B. Stieger, and P. J. Meier. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc. Natl. Acad. Sci. 94:10346–10350 (1997).

    Google Scholar 

  7. T. Abe, M. Kakyo, H. Sakagami, T. Tokui, T. Nishio, M. Tanemoto H. Nomura, S. C. Hebert, S. Matsuno, H. Kondo, and H. Yawo. Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. J. Biol. Chem. 273:22395–22401 (1998).

    Google Scholar 

  8. T. Sekine, N. Watanabe, M. Hosoyamada, Y. Kanai, and H. Endou. Expression cloning and characterization of a novel multispecific organic anion transporter. J. Biol. Chem. 272:18526–18529 (1997).

    Google Scholar 

  9. T. Sekine, S. H. Cha, M. Tsuda, N. Apiwattanakul, N. Nakajima, Y. Kanai, and H. Endou. Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett. 429:179–182 (1998).

    Google Scholar 

  10. H. Kusuhara, T. Sekine, T. N. Utsunomiya, M. Tsuda, R. Kojima, S. H. Cha, Y. Sugiyama, Y. Kanai, and E. Endou. Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J. Biol. Chem. 274:13675–13680 (1999).

    Google Scholar 

  11. B. Hagenbuch and P. J. Meier. Sinusoidal (basolateral) bile salt uptake systems of hepatocytes. Semin. Liver. Dis. 16:129–136 (1996).

    Google Scholar 

  12. K. Sathirakul, H. Suzuki, T. Yamada, M. Hanano, and Y. Sugiyama. Multiple transport systems for organic anions across the bile canalicular membrane. J. Pharmacol. Exp. Ther. 268:65–73 (1994).

    Google Scholar 

  13. R. P. J. Oude Elferink, D. K. F. Meijer, F. Kuipers, P. L. M. Jansen, A. K. Groen, and G. M. M. Groothuis. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochem. Biophys. Acta. 1241:215–268 (1995).

    Google Scholar 

  14. S. Hosokawa, O. Tagaya, T. Mikami, Y. Nozaki, A. Kawaguchi, K. Yamatsu, and M. Shamoto. A new rat mutant with chronic conjugated hyperbilirubinemia and renal glomerular lesions. Lab. Anim. Sci. 42:27–34 (1992).

    Google Scholar 

  15. H. Kusuhara, H. Suzuki, and Y. Sugiyama. The role of P-glyco-protein and canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs. J. Pharm. Sci. 87:1025–1040 (1998).

    Google Scholar 

  16. H. Suzuki, and Y. Sugiyama. Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2. Semin. Liver. Dis. 18:359–376 (1998).

    Google Scholar 

  17. H. Kouzuki, H. Suzuki, K. Ito, R. Ohashi, and Y. Sugiyama. Contribution of sodium taurocholate cotransporting polypeptide to the uptake of its possible substrates into rat hepatocytes. J. Pharmacol. Exp. Ther. 286:1043–1050 (1998).

    Google Scholar 

  18. H. Kouzuki, H. Suzuki, K. Ito, R. Ohashi, and Y. Sugiyama. Contribution of organic anion transporting polypeptide to uptake of its possible substrates into rat hepatocytes. J. Pharmacol. Exp. Ther. 288:627–634 (1999).

    Google Scholar 

  19. O. H. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with the folin phenol reagent. J. Biol. Chem. 193:265–275 (1951).

    Google Scholar 

  20. K. Yamaoka, Y. Tanigawara, T. Nakagawa, and T. Uno. A pharmacokinetic analysis program (MULTI) for microcomputer. J. Pharmacobio-Dyn. 4:879–885 (1981).

    Google Scholar 

  21. D. W. Yesair, and C. B. Coutinho. Method for extraction and separation of drugs and metabolites from biological tissue. Biochem. Pharmacol. 19:1569–1578 (1970).

    Google Scholar 

  22. D. Liang, B. Hagenbuch, B. Stieger, and P. J. Meier. Parallel decrease of Na+-taurocholate cotransport and its encoding mRNA in primary cultures of rat hepatocytes. Hepatol. 18:1162–1166 (1993).

    Google Scholar 

  23. M. Ishigami, T. Tokui, T. Komai, K. Tsukahara, M. Yamazaki, and Y. Sugiyama. Evaluation of the uptake of pravastatin by perfused rat liver and primary cultured rat hepatocytes. Pharm. Res. 12:1741–1745 (1995).

    Google Scholar 

  24. E. C. Torchia, R. J. Shapiro, and L. B. Agellon. Reconstitution of bile acid transport in the rat hepatoma McArdle RH-7777 cell line. Hepatology. 24:206–211 (1996).

    Google Scholar 

  25. M. S. Anwer and D. Hegner. Effect of Na+ on bile acid uptake by isolated rat hepatocytes. Hoppe-Seyler's Z Physiol. Chem. 359:181–192 (1978).

    Google Scholar 

  26. G. A. Kullak-Ublick, B. Hagenbuch, B. Stieger, A. W. Wolkoff, and P. J. Meier. Functional characterization of the basolateral rat liver organic anion transporting polypeptide. Hepatology 20:411–416 (1994).

    Google Scholar 

  27. H. Kouzuki, H. Suzuki, B. Stieger, P. J. Meier and Y. Sugiyama. Characterization of the transport properties of organic anion transporting polypeptide (oatp1) and Na+/taurocholate cotransporting polypeptide (Ntcp): Comparative studies on the inhibitory effect of their possible substrates in hepatocytes and cDNA-transfected COS-7 cells. J. Pharmacol. Exp. Ther. 292:505–511 (2000).

    Google Scholar 

  28. N. Apiwattanakul, T. Sekine, A. Chairoungdua, Y. Kanai, N. Nakajima, S. Sophasan, and H. Endou. Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes. Mol. Pharmacol. 55:847–854 (1999).

    Google Scholar 

  29. D. W. Yesair, M. Callahan, L. Remington, and C. J. Kensler. Role of the enterohepatic cycle of indomethacin on its metabolism, distribution in tissues and its excretion by rats, dogs and monkeys. Biochem. Pharmacol. 19:1579–1590 (1970).

    Google Scholar 

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Hirokazu Kouzuki, Hiroshi Suzuki & Yuichi Sugiyama

  2. Japan Science and Technology Corporation, Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan

    Hiroshi Suzuki

  3. Japan Science and Technology Corporation, Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan

    Yuichi Sugiyama

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  1. Hirokazu Kouzuki
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Kouzuki, H., Suzuki, H. & Sugiyama, Y. Pharmacokinetic Study of the Hepatobiliary Transport of Indomethacin. Pharm Res 17, 432–438 (2000). https://doi.org/10.1023/A:1007576903935

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