This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chu, X.-Y. Articles by Sugiyama, Y. Search for Related Content PubMed PubMed Citation Articles by Chu, X.-Y. Articles by Sugiyama, Y.

Biliary Excretion Mechanism of CPT-11 and Its Metabolites in Humans: Involvement of Primary Active Transporters¹

Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [X-Y. C, Y. K., K. U., H. S., K. N., Y. S.], and Toxicology Laboratory, SRI International, Menlo Park, California 94025-3943 [C. A. T., V. W., J. E. D., R. F., C. E. G.]

After administration of CPT-11, a camptothecin derivative exhibiting a wide spectrum of antitumor activity, dose-limiting gastrointestinal toxicity with great interpatient variability is observed. Because the biliary excretion is a major elimination pathway for CPT-11 and its metabolites [an active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and its glucuronide, SN38-Glu], several hypotheses for the toxicity involve biliary excretion. Here, we investigated whether primary active transport is involved in the biliary excretion of anionic forms of CPT-11 and its metabolites in humans using bile canalicular membrane vesicles (cMVs). Uptake of the carboxylate form of CPT-11 and the carboxylate and lactone forms of SN38-Glu by cMVs prepared from five human liver samples was ATP dependent. The concentration dependence of the ATP-dependent uptake of the carboxylate form of CPT-11 and SN38-Glu suggests the involvement of at least two saturable transport components, both with lower affinity and higher capacity than in rats. The ATP-dependent uptake of the carboxylate form of SN-38 showed a single saturable component but was detectable only in one human cMV sample. Both carboxylate and lactone forms of SN38-Glu uptake also showed a large intersample variability, although the variability was less than that observed for the carboxylate form of SN-38. On the other hand, the carboxylate form of CPT-11 exhibited much less variability. The carboxylate forms of SN38-Glu and SN-38 almost completely inhibited the ATP-dependent uptake of leukotriene C₄, a well-known substrate of canalicular multispecific organic anion transporter, whereas the inhibition by the carboxylate form of CPT-11 was not as marked. Thus, multiple primary active transport systems are responsible for the biliary excretion of CPT-11 and its metabolites, and the major transport system for CPT-11 differs from that for the other two compounds. A greater degree of inter-cMV variability in the uptake of SN-38 and SN38-Glu may imply that interindividual variability in biliary excretion of these metabolites might contribute to interpatient variability in the toxicity caused by CPT-11.

¹ This work was supported in part by a Grant-in Aid for Scientific Research provided by the Ministry of Education, Science, Sports and Culture of Japan and in part by a Grant for Cancer Research from the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed, at Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Received 5/11/98. Accepted 9/16/98.

This article has been cited by other articles:

				R. S. Midgley, D. J. Kerr, K. T. Flaherty, J. P. Stevenson, S. E. Pratap, K. M. Koch, D. A. Smith, M. Versola, R. A. Fleming, C. Ward, et al. A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan Ann. Onc., December 1, 2007; 18(12): 2025 - 2029. [Abstract] [Full Text] [PDF]

				X.-X. Yang, Z.-P. Hu, A.-L. Xu, W. Duan, Y.-Z. Zhu, M. Huang, F.-S. Sheu, Q. Zhang, J.-S. Bian, E. Chan, et al. A Mechanistic Study on Reduced Toxicity of Irinotecan by Coadministered Thalidomide, a Tumor Necrosis Factor-{alpha} Inhibitor J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 82 - 104. [Abstract] [Full Text] [PDF]

				M. Michael, M. Thompson, R. J. Hicks, P. L. Mitchell, A. Ellis, A. D. Milner, J. Di Iulio, A. M. Scott, V. Gurtler, J. M. Hoskins, et al. Relationship of Hepatic Functional Imaging to Irinotecan Pharmacokinetics and Genetic Parameters of Drug Elimination J. Clin. Oncol., September 10, 2006; 24(26): 4228 - 4235. [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]

				M. D. Prados, W.K.A. Yung, K. A. Jaeckle, H. I. Robins, M. P. Mehta, H. A. Fine, P. Y. Wen, T. F. Cloughesy, S. M. Chang, M. K. Nicholas, et al. Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American Brain Tumor Consortium study Neuro-oncol, January 1, 2004; 6(1): 44 - 54. [Abstract] [PDF]

				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]

				J. D. Chester, S. P. Joel, S. L. Cheeseman, G. D. Hall, M. S. Braun, J. Perry, T. Davis, C. J. Button, and M. T. Seymour Phase I and Pharmacokinetic Study of Intravenous Irinotecan Plus Oral Ciclosporin in Patients With Fluorouracil-Refractory Metastatic Colon Cancer J. Clin. Oncol., March 15, 2003; 21(6): 1125 - 1132. [Abstract] [Full Text] [PDF]

				Y. Xu and M. A. Villalona-Calero Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity Ann. Onc., December 1, 2002; 13(12): 1841 - 1851. [Abstract] [Full Text] [PDF]

				F. R. Luo, P. V. Paranjpe, A. Guo, E. Rubin, and P. Sinko Intestinal Transport of Irinotecan in Caco-2 Cells and MDCK II Cells Overexpressing Efflux Transporters Pgp, cMOAT, and MRP1 Drug Metab. Dispos., July 1, 2002; 30(7): 763 - 770. [Abstract] [Full Text] [PDF]

				M. Itoda, Y. Saito, A. Soyama, M. Saeki, N. Murayama, S. Ishida, K. Sai, M. Nagano, H. Suzuki, Y. Sugiyama, et al. Polymorphisms in the ABCC2 (cMOAT/MRP2) Gene Found in 72 Established Cell Lines Derived from Japanese Individuals: An Association between Single Nucleotide Polymorphisms in the 5'-Untranslated Region and Exon 28 Drug Metab. Dispos., April 1, 2002; 30(4): 363 - 364. [Abstract] [Full Text] [PDF]

				M. J. Ratain Irinotecan Dosing: Does the CPT in CPT-11 Stand for "Can't Predict Toxicity"? J. Clin. Oncol., January 1, 2002; 20(1): 7 - 8. [Full Text] [PDF]

				R. H.J. Mathijssen, J. Verweij, M. J.A. de Jonge, K. Nooter, G. Stoter, and A. Sparreboom Impact of Body-Size Measures on Irinotecan Clearance: Alternative Dosing Recommendations J. Clin. Oncol., January 1, 2002; 20(1): 81 - 87. [Abstract] [Full Text] [PDF]

				K. Sai, N. Kaniwa, S. Ozawa, and J.-i. Sawada A New Metabolite of Irinotecan in Which Formation Is Mediated by Human Hepatic Cytochrome P-450 3a4 Drug Metab. Dispos., November 1, 2001; 29(11): 1505 - 1513. [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]

				S. Okuno, M. Harada, T. Yano, S. Yano, S. Kiuchi, N. Tsuda, Y. Sakamura, J. Imai, T. Kawaguchi, and K. Tsujihara Complete Regression of Xenografted Human Carcinomas by Camptothecin Analogue-Carboxymethyl Dextran Conjugate (T-0128) Cancer Res., June 1, 2000; 60(11): 2988 - 2995. [Abstract] [Full Text] [PDF]

				E. Hinoshita, T. Uchiumi, K.-i. Taguchi, N. Kinukawa, M. Tsuneyoshi, Y. Maehara, K. Sugimachi, and M. Kuwano Increased Expression of an ATP-binding Cassette Superfamily Transporter, Multidrug Resistance Protein 2, in Human Colorectal Carcinomas Clin. Cancer Res., June 1, 2000; 6(6): 2401 - 2407. [Abstract] [Full Text]

				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]

				C. J. van Groeningen, W. J. F. Van der Vijgh, J. J. Baars, H. Stieltjes, K. Huibregtse, and H. M. Pinedo Altered Pharmacokinetics and Metabolism of CPT-11 in Liver Dysfunction: A Need for Guidelines Clin. Cancer Res., April 1, 2000; 6(4): 1342 - 1346. [Abstract] [Full Text]

				Z.-S. Chen, T. Kawabe, M. Ono, S. Aoki, T. Sumizawa, T. Furukawa, T. Uchiumi, M. Wada, M. Kuwano, and S.-I. Akiyama Effect of Multidrug Resistance-Reversing Agents on Transporting Activity of Human Canalicular Multispecific Organic Anion Transporter Mol. Pharmacol., December 1, 1999; 56(6): 1219 - 1228. [Abstract] [Full Text]

				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]

				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]