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Journal of Pharmacology and Experimental Therapeutics

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OtherDRUG METABOLISM AND DISPOSITION

Multispecific Organic Anion Transporter Is Responsible for the Biliary Excretion of the Camptothecin Derivative Irinotecan and its Metabolites in Rats

Xiao-Yan Chu, Yukio Kato, Kayoko Niinuma, Ken-Ichi Sudo, Hideo Hakusui and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics April 1997, 281 (1) 304-314;
Xiao-Yan Chu
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Yukio Kato
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Kayoko Niinuma
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Ken-Ichi Sudo
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Hideo Hakusui
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Yuichi Sugiyama
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Abstract

Irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11), is a potent anticancer drug that is increasingly used in chemotherapy. A frequent limiting side effect involves gastrointestinal toxicity (diarrhea), which is thought to be related to the biliary excretion of CPT-11 and its metabolites. Accordingly, the biliary excretion mechanisms for both the lactone and carboxylate forms of CPT-11 and its metabolites, SN-38 and its glucuronide (SN38-Glu), were investigated using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR), with the latter being mutant rats with a genetic deficiency of the canalicular multispecific organic anion transporter. After i.v. administration of CPT-11, the biliary excretion clearance, defined as the biliary excretion rate normalized to the hepatic concentration, of both the lactone and carboxylate forms of SN38-Glu was much lower in EHBR. The biliary excretion clearance for the carboxylate form of both CPT-11 and SN-38 was also substantially smaller in EHBR and showed marked saturation with increasing dose only in SD rats. On the other hand, the biliary excretion clearance for the lactone forms of CPT-11 and SN-38 showed only a minimal difference in EHBR, compared with SD rats. These results suggest that, for the carboxylate form of CPT-11 and SN-38 and the carboxylate and lactone forms of SN38-Glu, there exists a specific transport system at the bile canalicular membrane that is deficient in EHBR. To confirm this hypothesis, the uptake of these substrates by isolated hepatic canalicular membrane vesicles (CMV) was examined. ATP-dependence was clearly observed for the uptake of these four compounds by CMV prepared from SD rats but not by CMV from EHBR. In addition, the compounds inhibited the ATP-dependent uptake ofS-(2,4-dinitrophenyl) glutathione by CMV from SD rats, in a concentration-dependent manner. These results suggest that the biliary excretion of the carboxylate forms of CPT-11 and SN-38 and the carboxylate and lactone forms of SN38-Glu is mediated by the multispecific organic anion transporter, which is deficient in EHBR.

Footnotes

  • Send reprint requests to: Dr. Yuichi Sugiyama, Faculty of Pharmaceutical Sciences, University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.

  • ↵1 This study was supported in part by a Grant-in-Aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan.

  • Abbreviations:
    AUC
    area under the curve
    Cbile/Cliver
    bile-to-liver concentration ratio
    CLbile,h
    biliary excretion clearance defined with respect to the hepatic concentration of the drug
    CLbile,p
    biliary excretion clearance defined with respect to the plasma concentration of the drug
    CLr
    urinary excretion clearance
    cMOAT
    canalicular multispecific organic anion transporter
    CMV
    canalicular membrane vesicle(s)
    CPT
    camptothecin
    CPT-11
    7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin
    DNP-SG
    S-(2,4-dinitrophenyl) glutathione
    EHBR
    Eisai hyperbilirubinemic rat(s)
    HPLC
    high-performance liquid chromatography
    SD
    Sprague-Dawley
    SN38-Glu
    SN-38 glucuronide
    • Received May 10, 1996.
    • Accepted December 6, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 1
1 Apr 1997
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OtherDRUG METABOLISM AND DISPOSITION

Multispecific Organic Anion Transporter Is Responsible for the Biliary Excretion of the Camptothecin Derivative Irinotecan and its Metabolites in Rats

Xiao-Yan Chu, Yukio Kato, Kayoko Niinuma, Ken-Ichi Sudo, Hideo Hakusui and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics April 1, 1997, 281 (1) 304-314;

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OtherDRUG METABOLISM AND DISPOSITION

Multispecific Organic Anion Transporter Is Responsible for the Biliary Excretion of the Camptothecin Derivative Irinotecan and its Metabolites in Rats

Xiao-Yan Chu, Yukio Kato, Kayoko Niinuma, Ken-Ichi Sudo, Hideo Hakusui and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics April 1, 1997, 281 (1) 304-314;
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