Abstract
Purpose. To ameliorate the late-onset of severe gastrointestinal toxicity provoked by irinotecan (CPT-11), which may be related to the biliary excretion of CPT-11 and/or its metabolites.
Methods. Effects of probenecid, an inhibitor of MRP2/ABCC2, on the biliary excretion and mucosal intestinal tissue concentration of CPT-11 and its metabolites were examined in rats. CPT-11-induced late-onset gastrointestinal toxicity was also evaluated.
Results. Coadministration of probenecid reduced the biliary excretion of CPT-11, an active metabolite (SN-38) and its glucuronide by half with a concomitant increase in their plasma concentration. When the dose of CPT-11, in the presence of probenecid, was set at half that in its absence, the plasma SN-38 concentration was maintained at the same level as the control, whereas the mucosal intestinal tissue concentration of SN-38 was reduced. Under this condition, CPT-11-induced watery diarrhea, changes in intestinal marker enzymes and body weight reduction were much less in the probenecid-treated group, although the degree of bone marrow suppression was almost the same as that in the control.
Conclusions. Coadministration of probenecid with a reduced dose of CPT-11 potently reduces both SN-38 exposure and CPT-11-induced late-onset toxicity in gastrointestinal tissues, possibly by inhibiting the biliary excretion of CPT-11 and/or its metabolites.
Similar content being viewed by others
REFERENCES
T. Andoh, K. Ishii, and Y. Suzuki. Characterization of a mammalian mutant with a camptothecin-resistant DNA topoisomerase I. Proc. Natl. Acad. USA 84:5565–5569 (1987).
L. P. Rivory, M. R. Riou, J. Robert, and S. M. Pond. Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by human liver carboxylesterase. Biochem. Pharmacol. 52:1103–1111 (1996).
R. Atsumi, W. Suzuki, and H. Hakusui. Identification of the metabolites of irinotecan, a new derivative of camptothecin, in rat bile and its biliary excretion. Xenobiotica 21:1159–1169 (1991).
R. Ohno, K. Okada, T. Masaoka, A. Kuramoto, T. Arima, Y. Yoshida, H. Ariyoshi, M. Ichimaru, Y. Sasaki, M. Oguro, Y. Ito, Y. Morishima, S. Yokomaku, and K. Ota. An early phase II study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma. J. Clin. Oncol. 8:1907 (1990).
S. Kudoh, M. Fukuoka, N. Masuda, A. Yoshikawa, Y. Kusunoki, K. Mastui, S.-I. Negoro, N. Takifuji, K. Nakagawa, T. Hirashima, T. Yana, and M. Takada. Relationship between the pharmacokinetics of irinotecan and diarrhea during combination chemotherapy of cisplatin. Jpn. J. Cancer Res. 86:406–413 (1995).
S. Negoro, M. Fukuoka, N. Masuda, M. Takada, Y. Kusunoki, K. Mastui, N. Takifuji, S. Kudoh, H. Nitani, and T. Taguchi. Phase I study of weekly intravenous infusion of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J. Natl. Cancer Inst. 83:1164–1168 (1991).
K. Takasuna, Y. Kasai, Y. Kitano, K. Mori, K. Kakihata, M. Hirohashi, and M. Nomura. Study on the mechanisms of diarrhea induced by a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats. Folia. Pharmacol. Jpn. 105:447–460 (1995).
E. Gupta, T. M. Lestingi, R. Mick, J. Ramirez, E. E. Vokes, and J. Ratain. Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Res. 54:3723–3725 (1994).
K. Takasuna, T. Hagiwara, M. Hirohashi, M. Kato, M. Nomura, E. Nagai, T. Yokoi, and T. Kamataki. Involvement of ??glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res. 56:3752–3757 (1996).
K. Takasuna, T. Hagiwara, M. Hirohashi, M. Kato, M. Nomura, E. Nagai, T. Yokoi, and T. Kamataki. Inhibition of intestinal microflora β-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats. Cancer Chemother. Pharmacol. 42:280–286 (1998).
K. Takasuna, Y. Kasai, Y. Kitano, K. Mori, R. Kobayashi, T. Hagiwara, K. Kakihata, M. Hirohashi, M. Nomura, E. Nagai, and T. Kamataki. Prospective effect of Kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats. Jpn. J. Cancer Res. 86:978–984 (1995).
N. Kaneda and T. Yokokura. Nonlinear pharmacokinetics of CPT-11 in rats. Cancer Res. 50:1721–1725 (1990).
F. Lokieo, P. Canal, C. Gay, E. Chatelut, J. P. Armand, H. Roche, R. Bugat, E. Goncalves, and A. Mathieu-Boue. Pharmacokinetics of irinotecan and its metabolites in human blood, bile, urine. Cancer Chemother. Pharmacol. 36:79–82 (1995).
F. Ahmed, V. Vya, A. Cornfield, S. Goodin, T. S. Ravikumar, E. Rubin, and E. Gupta. In vitro activation of irinotecan to SN-38 by human liver and intestine. Anticancer Res. 19:2067–2072 (1999).
X.-Y. Chu, Y. Kato, and Y. Sugiyama. Multiplicity of biliary excretion mechanisms of irinotecan, CPT-11, and its metabolites in rats. Cancer Res. 57:1934–1938 (1997).
X.-Y. Chu, Y. Kato, K. Niinuma, K. 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).
X.-Y. Chu, Y. Kato, K. Ueda, H. Suzuki, K. Niinuma, C. A. Tyson, V. Weizer, J. E. Dabb, R. Froehlich, C. E. Green, and Y. Sugiyama. Biliary excretion mechanism of CPT-11 and its metabolites in humans: Involvement of primary active transporters. Cancer Res. 58:5137–5143 (1998).
K. Ueda, Y. Kato, K. Komatsu, and Y. Sugiyama. Inhibition of the biliary excretion of methotrexate by probenecid in rats: Quantitative prediction of the interaction from in vitro data. J. Pharmacol. Exp. Ther. 297:1036–1043 (2001).
B.-M. Emanuelsson, B. Beermann, and L. K. Paalzow. Nonlinear elimination and protein binding of probenecid. Eur. J. Clin. Pharmacol. 32:395–401 (1987).
M. Saxena and G. B. Henderson. ATP-dependent efflux of 2,4-dinitrophenyl-S-glutathione. J. Biol. Chem. 270:5312–5319 (1995).
K. Yachi, Y. Sugiyama, Y. Sawada, T. Iga, Y. Ikeda, and G. Toda, and M. Hanano. Characterization of rose bengal binding to sinusoidal and canalicular plasma membrane from rat liver. Biochim. Biophys. Acta 978:1–7 (1989).
H. G. Klemperer. and G. R. Haynes Thymidine kinase in rat liver during development. Biochem. J. 108:541–546 (1968).
K. Yamaoka, Y. Tanigawara, T. Nakagawa, and T. Uno. A pharmacokinetic analysis program (MULTI) for microcomputer, J. Pharmacobio.-Dyn. 4:879–885 (1981).
K. J. Ullrich and G. Rumrich. Luminal transport step of paraaminohippurate (PAH):transport from PAH-loaded proximal tubular cells into the lumen of the rat kidney in vivo. Pflugers. Arch. 433:735–743 (1997).
S. Terashita, T. Sawamoto, S. Deguchi, Y. Tokuma, and T. Hata. Sex-dependent and independent renal excretion of nilvadipine metabolites in rat;evidence for a sex-dependent active secretion in kidney. Xenobiotica 25:37–47 (1995).
R. Masereeuw, F. G. Russel, and D. S. Miller. Multiple pathways of organic anion secretion in renal proximal tuble revealed confocal microscopy. Am. J. Physiol. 271:F1173–F1179 (1996).
J. G. Slatter, P. Su, J. P. Sams, L. J. Schaaf, and L. C. Wienkers. Bioactivation of the anticancer agent CPT-11 to SN-38 by human hepatic microsomal carboxylesterases and the in vitro assessment of potential drug interactions. Drug Metab. Dispos. 25:1157–1164 (1997).
T. P. Schaub, J. Kartenbeck, J. Konig, H. Spring, J. Dorsam, G. Staehler, S. Storkel, W. F. Thon, and D. Keppler. Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J. Am. Soc. Nephrol. 10:1159–1169 (1999).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Horikawa, M., Kato, Y. & Sugiyama, Y. Reduced Gastrointestinal Toxicity Following Inhibition of the Biliary Excretion of Irinotecan and Its Metabolites by Probenecid in Rats. Pharm Res 19, 1345–1353 (2002). https://doi.org/10.1023/A:1020358910490
Issue Date:
DOI: https://doi.org/10.1023/A:1020358910490