![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 281, Issue 1, 304-314, 1997
Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo,
Japan (X.-Y.C., Y.K., K.N., Y.S.), and
Drug Metabolism and Analytical
Chemistry Research Center, Developmental Research Laboratories, Daiichi
Pharmaceutical Co., Ltd., Tokyo, Japan (K.-I.S., H.H.)
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 of
S-(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.
This article has been cited by other articles:
|
|
 |
|
  S. Owatari, S. Akune, M. Komatsu, R. Ikeda, S. D. Firth, X.-F. Che, M. Yamamoto, K. Tsujikawa, M. Kitazono, T. Ishizawa, et al. Copper-Transporting P-Type ATPase, ATP7A, Confers Multidrug Resistance and Its Expression Is Related to Resistance to SN-38 in Clinical Colon Cancer Cancer Res., May 15, 2007; 67(10): 4860 - 4868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Zamek-Gliszczynski, K. A. Hoffmaster, J. E. Humphreys, X. Tian, K.-i. Nezasa, and K. L. R. Brouwer Differential Involvement of Mrp2 (Abcc2) and Bcrp (Abcg2) in Biliary Excretion of 4-Methylumbelliferyl Glucuronide and Sulfate in the Rat J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 459 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. H. Vlaming, K. Mohrmann, E. Wagenaar, D. R. de Waart, R. P. J. O. Elferink, J. S. Lagas, O. van Tellingen, L. D. Vainchtein, H. Rosing, J. H. Beijnen, et al. Carcinogen and Anticancer Drug Transport by Mrp2 in Vivo: Studies Using Mrp2 (Abcc2) Knockout Mice J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 319 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Y. Chu, J. R. Strauss, M. A. Mariano, J. Li, D. J. Newton, X. Cai, R. W. Wang, J. Yabut, D. P. Hartley, D. C. Evans, et al. Characterization of Mice Lacking the Multidrug Resistance Protein Mrp2 (Abcc2) J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 579 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Shimizu, K. Fuse, K. Okudaira, R. Nishigaki, K. Maeda, H. Kusuhara, and Y. Sugiyama CONTRIBUTION OF OATP (ORGANIC ANION-TRANSPORTING POLYPEPTIDE) FAMILY TRANSPORTERS TO THE HEPATIC UPTAKE OF FEXOFENADINE IN HUMANS Drug Metab. Dispos., October 1, 2005; 33(10): 1477 - 1481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Tallman, J. K. Ritter, and P. C. Smith DIFFERENTIAL RATES OF GLUCURONIDATION FOR 7-ETHYL-10-HYDROXY-CAMPTOTHECIN (SN-38) LACTONE AND CARBOXYLATE IN HUMAN AND RAT MICROSOMES AND RECOMBINANT UDP-GLUCURONOSYLTRANSFERASE ISOFORMS Drug Metab. Dispos., July 1, 2005; 33(7): 977 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nozawa, H. Minami, S. Sugiura, A. Tsuji, and I. Tamai ROLE OF ORGANIC ANION TRANSPORTER OATP1B1 (OATP-C) IN HEPATIC UPTAKE OF IRINOTECAN AND ITS ACTIVE METABOLITE, 7-ETHYL-10-HYDROXYCAMPTOTHECIN: IN VITRO EVIDENCE AND EFFECT OF SINGLE NUCLEOTIDE POLYMORPHISMS Drug Metab. Dispos., March 1, 2005; 33(3): 434 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yu, W. D. Shannon, M. A. Watson, and H. L. McLeod Gene Expression Profiling of the Irinotecan Pathway in Colorectal Cancer Clin. Cancer Res., March 1, 2005; 11(5): 2053 - 2062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kobayashi, H. Saitoh, M. Kobayashi, K. Tadano, Y. Takahashi, and T. Hirano Cyclosporin A, but Not Tacrolimus, Inhibits the Biliary Excretion of Mycophenolic Acid Glucuronide Possibly Mediated by Multidrug Resistance-Associated Protein 2 in Rats J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1029 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Y. Chu, S.-E. W. Huskey, M. P. Braun, B. Sarkadi, D. C. Evans, and R. Evers Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3 J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 156 - 164. [Abstract] [Full Text]
|
|
|
|
 |
|
 N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama Impact of Drug Transporter Studies on Drug Discovery and Development Pharmacol. Rev., September 1, 2003; 55(3): 425 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. J. Mathijssen, S. Marsh, M. O. Karlsson, R. Xie, S. D. Baker, J. Verweij, A. Sparreboom, and H. L. McLeod Irinotecan Pathway Genotype Analysis to Predict Pharmacokinetics Clin. Cancer Res., August 1, 2003; 9(9): 3246 - 3253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Crews, C. F. Stewart, D. Jones-Wallace, S. J. Thompson, P. J. Houghton, R. L. Heideman, M. Fouladi, D. C. Bowers, M. M. Chintagumpala, and A. Gajjar Altered Irinotecan Pharmacokinetics in Pediatric High-Grade Glioma Patients Receiving Enzyme-inducing Anticonvulsant Therapy Clin. Cancer Res., July 1, 2002; 8(7): 2202 - 2209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ikegami, L. Ha, K. Arimori, P. Latham, K. Kobayashi, S. Ceryak, Y. Matsuzaki, and B. Bouscarel Intestinal Alkalization As a Possible Preventive Mechanism in Irinotecan (CPT-11)-induced Diarrhea Cancer Res., January 1, 2002; 62(1): 179 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Gamcsik, M. S. Kasibhatla, D. J. Adams, J. L. Flowers, O. M. Colvin, G. Manikumar, M. Wani, M. E. Wall, G. Kohlhagen, and Y. Pommier Dual Role of Glutathione in Modulating Camptothecin Activity: Depletion Potentiates Activity, but Conjugation Enhances the Stability of the Topoisomerase I-DNA Cleavage Complex Mol. Cancer Ther., November 1, 2001; 1(1): 11 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. J. 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., August 1, 2001; 7(8): 2182 - 2194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Fromm, H.-M. Kauffmann, P. Fritz, O. Burk, H. K. Kroemer, R. W. Warzok, M. Eichelbaum, W. Siegmund, and D. Schrenk The Effect of Rifampin Treatment on Intestinal Expression of Human MRP Transporters Am. J. Pathol., November 1, 2000; 157(5): 1575 - 1580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kato, T. Igarashi, Y. Sugiyama, and A. Nishino Both cMOAT/MRP2 and Another Unknown Transporter(s) Are Responsible for the Biliary Excretion of Glucuronide Conjugate of the Nonpeptide Angiotensin II Antagonist, Telmisaltan Drug Metab. Dispos., October 1, 2000; 28(10): 1146 - 1148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Slatter, L. J. Schaaf, J. P. Sams, K. L. Feenstra, M. G. Johnson, P. A. Bombardt, K. S. Cathcart, M. T. Verburg, L. K. Pearson, L. D. Compton, et al. Pharmacokinetics, Metabolism, and Excretion of Irinotecan (CPT-11) Following I.V. Infusion of [14C]CPT-11 in Cancer Patients Drug Metab. Dispos., April 1, 2000; 28(4): 423 - 433. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. S. Friedman, W. P. Petros, A. H. Friedman, L. J. Schaaf, T. Kerby, J. Lawyer, M. Parry, P. J. Houghton, S. Lovell, K. Rasheed, et al. Irinotecan Therapy in Adults With Recurrent or Progressive Malignant Glioma J. Clin. Oncol., May 1, 1999; 17(5): 1516 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Niinuma, Y. Kato, H. Suzuki, C. A. Tyson, V. Weizer, J. E. Dabbs, R. Froehlich, C. E. Green, and Y. Sugiyama Primary active transport of organic anions on bile canalicular membrane in humans Am J Physiol Gastrointest Liver Physiol, May 1, 1999; 276(5): G1153 - G1164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z.-S. Chen, T. Furukawa, T. Sumizawa, K. Ono, K. Ueda, K. Seto, and S.-I. Akiyama ATP-Dependent Efflux of CPT-11 and SN-38 by the Multidrug Resistance Protein (MRP) and Its Inhibition by PAK-104P Mol. Pharmacol., May 1, 1999; 55(5): 921 - 928. [Abstract] [Full Text]
|
|
|
|
|
|
X.-Y. Chu, Y. Kato, and Y. Sugiyama Possible Involvement of P-Glycoprotein in Biliary Excretion of CPT-11 in Rats Drug Metab. Dispos., April 1, 1999; 27(4): 440 - 441. [Abstract] [Full Text]
|
|
|
|
|
|
S. Akhteruzzaman, Y. Kato, A. Hisaka, and Y. Sugiyama Primary Active Transport of Peptidic Endothelin Antagonists by Rat Hepatic Canalicular Membrane J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 575 - 581. [Abstract] [Full Text]
|
|
|
|
|
|
X.-Y. Chu, H. Suzuki, K. Ueda, Y. Kato, S.-I. Akiyama, and Y. Sugiyama Active Efflux of CPT-11 and Its Metabolites in Human KB-Derived Cell Lines J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 735 - 741. [Abstract] [Full Text]
|
|
|
|
|
|
M. Homma, H. Suzuki, H. Kusuhara, M. Naito, T. Tsuruo, and Y. Sugiyama High-Affinity Efflux Transport System for Glutathione Conjugates on the Luminal Membrane of a Mouse Brain Capillary Endothelial Cell Line (MBEC4) J. Pharmacol. Exp. Ther., January 1, 1999; 288(1): 198 - 203. [Abstract] [Full Text]
|
|
|
|
|
|
H. Sasabe, Y. Kato, A. Tsuji, and Y. Sugiyama Stereoselective Hepatobiliary Transport of the Quinolone Antibiotic Grepafloxacin and Its Glucuronide in the Rat J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 661 - 668. [Abstract] [Full Text]
|
|
|
|
 |
|
 K. Ito, H. Suzuki, T. Hirohashi, K. Kume, T. Shimizu, and Y. Sugiyama Functional Analysis of a Canalicular Multispecific Organic Anion Transporter Cloned from Rat Liver J. Biol. Chem., January 16, 1998; 273(3): 1684 - 1688. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
