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Effect of P-Glycoprotein Modulator, Cyclosporin A, on the Gastrointestinal Excretion of Irinotecan and Its Metabolite SN-38 in Rats

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Abstract

Purpose. The purpose of this work was to investigate the role of the hepatic and intestinal P-glycoprotein (P-gp) and canalicular multispecific organic anion transporter /multidrug resistance-associated protein 2 (cMOAT/MRP2) on both biliary excretion and intestinal exsorption of irinotecan hydrochloride (CPT-11) and its metabolite, SN-38, in the lactone and carboxylate forms. Cyclosporin A (CsA) was used to modulate P-gp and cMOAT/MRP2.

Methods. The transcellular transport of CPT-11 and SN-38 was examined by using LLC-PK1 derivative cell lines transfected with murine mdr1a both in the absence or in the presence of CsA. The excretions of the compounds through the biliary and intestinal membrane routes were investigated by in situ perfusion technique.

Results. Basolateral-to-apical transport of CPT-11 lactone in L-mdr1a cells was significantly decreased by CsA (10 μM). The trans- cellular transport of SN-38 lactone showed similar behaviors as those of CPT-11 lactone. The biliary excretion and the intestinal exsorption of both forms of CPT-11 and SN-38 were significantly inhibited when the drug was co-administered with CsA.

Conclusions. The transports of CPT-11 and SN-38 via the biliary route seem to be essentially related with cMOAT/MRP2, whereas those of both compounds via the intestinal membrane seem to be related with P-gp.

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References

  1. Y. Kawato, M. Aonuma, Y. Hirota, H. Kuga, and K. Sato. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effects of CPT-11. Cancer Res. 51:4187–4191 (1991).

    PubMed  Google Scholar 

  2. A. Kojima, T. Shinkai, and N. Saijo. Cytogenetic effects of CPT-11 and its active metabolite, SN-38 on human. Jpn. J. Clin. Oncol. 23:116–122 (1993).

    PubMed  Google Scholar 

  3. M. Narita, E. Nagai, H. Hagiwara, M. Aburada, T. Yokoi, and T. Kamataki. Inhibition of beta-glucuronidase by natural glucuronides of kampo medicines using glucuronide of SN-38 (7-ethyl-10-hydroxycamptothecin) as a substrate. Xenobiotica 23:5–10 (1993).

    PubMed  Google Scholar 

  4. R. H. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A. Sparreboom. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin. Cancer Res. 7:2182–2194 (2001).

    PubMed  Google Scholar 

  5. W. Yamamoto, J. Verweiji, P. de Bruijin, M. J. de Jonge, and H. Takano. M. Nishiyama, M. Kurihara, and A. Sparreboom. Active transepithelial transport of irinotecan (CPT-11) and its metabolites by human intestinal Caco-2 cells. Anticancer Drugs 12:419–432 (2001).

    PubMed  Google Scholar 

  6. K. Arimori, N. Kuroki, A. Kumamoto, N. Tanoue, M. Nakano, E. Kumazawa, A. Tohgo, and M. Kikuchi. Excretion into Gastrointestinal tract of irinotecan lactone and carboxylate forms and their pharmacodynamics in rodents. Pharm. Res. 18:814–822 (2001).

    PubMed  Google Scholar 

  7. X.-Y. Chu, Y. Kato, K. Ueda, H. Suzuki, K. Niinuma, C. A. Tyson, V. Weizer, J. E. Dabbs, R. Froehlich, C. E. Green, and Y. Sugiyama. Biliary excretion mechanisms for CPT-11 and its metabolites in humans: involvement of primary active transporters. Cancer Res. 58:5137–5143 (1998).

    PubMed  Google Scholar 

  8. E. Gupta, A. R. Safa, X. Wang, and M. J. Ratain. Pharmacokinetic modulation of irinotecan and metabolites by cyclosporin A. Cancer Res. 56:1309–1314 (1996).

    PubMed  Google Scholar 

  9. X.-Y. Chu, Y. Kato, and Y. Sugiyama. Possible involvement of P-glycoprotein in biliary excretion of CPT-11 in rats. Drug Metab. Dispos. 27:440–441 (1999).

    PubMed  Google Scholar 

  10. M. Horikawa, Y. Kato, C. A. Tyson, and Y. Sugiyama. The potential for an interaction between MRP2 (ABCC2) and various therapeutic agents: probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites. Drug Metabol. Pharmacokinet. 17:23–33 (2002).

    Google Scholar 

  11. X.-Y. Chu, Y. Kato, K. Niinuma, K.-I. Sudo, H. Hakusui, and Y. Sugiyama. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J. Pharmacol. Exp. Ther. 281:304–314 (1997).

    PubMed  Google Scholar 

  12. Y. Liu, L. Huang, T. Hoffman, M. Gosland, and M. Vore. MDR1 substrates/modulators protect against beta-estradiol-17beta-D-glucuronide cholestasis in rat liver. Cancer Res. 56:4992–4997 (1996).

    PubMed  Google Scholar 

  13. A. Tomimaru, K. Arimori, N. Inotsume, and M. Nakano. Effect of activated charcoal and atropine on absorption and/or exsorption of organophosphorus compounds. J. Pharm. Pharmacol. 48:351–356 (1996).

    PubMed  Google Scholar 

  14. K. Arimori and M. Nakano. Transport of theophylline from blood to the intestinal lumen following i.v. administration to rats. J. Pharmacobio-Dyn. 8:324–327 (1985).

    PubMed  Google Scholar 

  15. L. P. Rivory, and J. Robert. 1994. Reversed-phase high-performance liquid chromatographic method for the simultaneous quantitation of the carboxylate and lactone forms of the camptothecin derivative irinotecan, CPT-11, and its metabolite SN-38 in plasma. J. Chromatogr. B Biomed. Appl. 661:133–141 (1994).

    PubMed  Google Scholar 

  16. X.-Y. Chu, H. Suzuki, K. Ueda, Y. Kato, and Y. Sugiyama. Active efflux of CPT-11 and its metabolites in human KB-derived cell lines. J. Pharmacol. Exp. Ther. 288:735–741 (1999).

    PubMed  Google Scholar 

  17. K. Ueda, N. Okamura, M. Hirai, Y. Tanigawara, T. Saeki, N. Kioka, and R. Hori. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J. Biol. Chem. 267:24248–24252 (1992).

    PubMed  Google Scholar 

  18. F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA 84:7735–7738 (1987).

    PubMed  Google Scholar 

  19. P. M. Gerk and M. Vore. Regulation of expression of the multidrug resistance-associate protein 2 (MRP2) and its role in drug disposition. J. Pharmacol. Exp. Ther. 302:407–415 (2002).

    PubMed  Google Scholar 

  20. J. W. Smit, A. H. Schinkel, M. Muller, B. Weert, and D. K. Meijer. Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with an mdr1a gene disruption. Hepatology 27:1056–1063 (1998).

    PubMed  Google Scholar 

  21. K. Arimori and M. Nakano. Drug exsorption from blood into the gastrointestinal tract. Pharm. Res. 15:371–376 (1998).

    PubMed  Google Scholar 

  22. K. Akimoto, A. Kawai, and K. Ohya. Kinetic studies of the hydrolysis and lactonization of camptothecin and its derivatives, CPT-11 and SN-38, in aqueous solution. Chem. Pharm. Bull. 42:2135–2138 (1994).

    Google Scholar 

  23. Y. Sugiyama, Y. Kato, and X-X. Chu. 1998. Multiplicity of biliary excretion mechanisms for the camptothecin derivative irinotecan (CPT-11), its metabolite SN-38, and its glucuronide: role of canalicular multispecific organic anion transporter and P-glycoprotein. Cancer Chemother. Pharmacol. 42(Suppl):S44-S49 (1998).

    PubMed  Google Scholar 

  24. X.-Y. Chu, Y. Kato, and Y. Sugiyama. Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats. Cancer Res. 57:1934–1938 (1997).

    PubMed  Google Scholar 

  25. K. Kobayashi, B. Bouscarel, Y. Matsuzaki, S. Ceryak, S. Kudoh, and H. Fromm. PH-dependent uptake of irinotecan and its active metabolite, SN-38, by intestinal cells. Int. J. Cancer 83:491–496 (1999).

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, Miyazaki Medical College, 5200 Kihara, Kiyotake-cho, Miyazaki-gun, Miyazaki, 889-1692, Japan

    Kazuhiko Arimori, Muneaki Hidaka, Tomomi Iwakiri, Keishi Yamasaki, Manabu Okumura, Hiroshige Ono & Norito Takamura

  2. Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Noriaki Kuroki & Masahiro Nakano

  3. PMS & Applied Clinical Development Department, Daiichi Pharmaceutical Co., Ltd., 16-1 Kyobashi 2-Chome, Chuo-ku, Tokyo, 104-8369, Japan

    Masahiko Kikuchi

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  1. Kazuhiko Arimori
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  2. Noriaki Kuroki
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Arimori, K., Kuroki, N., Hidaka, M. et al. Effect of P-Glycoprotein Modulator, Cyclosporin A, on the Gastrointestinal Excretion of Irinotecan and Its Metabolite SN-38 in Rats. Pharm Res 20, 910–917 (2003). https://doi.org/10.1023/A:1023847521767

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