Skip to main content

Advertisement

SpringerLink
Log in

Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of β-glucuronidase activity in intestinal lumen

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Irinotecan hydrochloride (CPT-11) is a useful drug for cancer chemotherapy but sometimes induces severe diarrhea clinically. CPT-11 is mainly activated to SN-38 by carboxylesterase (CES) and then detoxified to SN-38 glucuronide (SN-38G) by UDP-glucuronosyltransferase (UGT) in the liver. SN-38G is excreted via bile and de-conjugated to SN-38 by β-glucuronidase (β-GLU) in the intestinal content. In order to clarify the alleviative effect of antibiotics on CPT-11-induced diarrhea, we examined whether penicillin G and streptomycin (SM) alleviate CPT-11-induced delayed-onset diarrhea using three diarrheal models, i.e., Wistar rats with repeated dosing of CPT-11 (60 mg/kg/day i.v. for 4 consecutive days) and Wistar and Gunn rats with a single dosing of CPT-11 (200 and 20 mg/kg i.v., respectively). Gunn rats have an inherited deficiency of UGT1A and cannot conjugate SN-38 to SN-38G. Therefore, onset of CPT-11-induced diarrhea in Gunn rats is not affected by β-GLU activity. SM alleviated diarrhea in all three diarrheal models. The alleviation of diarrhea by SM in Gunn rats indicated that the effect of SM occurred by a mechanism other than the inhibition of β-GLU activity. SM decreased CPT-11 and/or SN-38 concentrations in intestinal tissues and alleviated epithelial damage from the ileum to colon. SM did not inhibit β-GLU activity in the cecal content. SM also inhibited the intestinal absorption of CPT-11 and decreased CES activity and increased UGT activity in the intestinal epithelium. These findings indicated that SM decreased the exposure of CPT-11 and SN-38 to the intestinal epithelium by inhibiting the absorption of CPT-11 from the intestinal lumen and the change of CES and UGT activities in the intestinal epithelium and alleviated delayed-onset diarrhea.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

CPT-11:

Irinotecan hydrochloride

SN-38:

7-ethyl-10-hydroxycamptothecin

SN-38G:

SN-38 glucuronide

CES:

Carboxylesterase

UGT:

UDP-glucuronosyltransferase

β-GLU:

β-glucuronidase

Cmax :

Maximum concentration

AUC:

Area under the concentration–time curve

MRT:

Mean resident time

CLtot :

Total clearance

Vdss :

Volume of distribution at steady state

t 1/2 :

Half-life

IS:

Internal standard

i.v.:

Intravenous(ly)

p.o.:

Oral(ly)

SM:

Streptomycin sulfate

PG:

Penicillin G potassium

SI:

Small intestine

References

  1. Abigerges D, Armand J-P, Chabot GG, da Costa L, Fadel E, Cote C, Hérait P, Gandia D (1994) Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 86:446–449

    Article  CAS  PubMed  Google Scholar 

  2. Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, Yokoyama A, Saitoh S, Shimokata K, Hasegawa Y (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60:6921–6926

    CAS  PubMed  Google Scholar 

  3. Atsumi R, Suzuki W, Hakusui H (1991) Identification of metabolites of irinotecan, a new derivative of camptothecin, in the rat bile and its biliary excretion. Xenobiotica 21:1159–1169

    Article  CAS  PubMed  Google Scholar 

  4. De Jong FA, Kehrer DFS, Mathijssen RHJ, Creemers GJ, de Bruijn P, van Schaik RHN, Planting AST, van der Gaast A, Eskens FAL, Janssen JTP, Ruit JB, Verweij J, Sparreboom A, de Jonge MJA (2006) Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study. Oncologist 11:944–954

    Article  PubMed  Google Scholar 

  5. Fukuoka M, Niitani H, Suzuki A, Motomiya M, Hasegawa K, Nishiwaki Y, Kuriyama T, Ariyoshi Y, Negoro S, Masuda N, Nakajima S, Taguchi T (1992) A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer (see comment citation in Medline). J Clin Oncol 10:16–20

    CAS  PubMed  Google Scholar 

  6. Furuta T, Yokokura T, Mutai M (1998) Antitumor activity of CPT-11 against rat Walker 256 carcinoma (in Japanese). Jpn J Cancer Chemother 15:2757–2760

    Google Scholar 

  7. Gandia D, Abigerges D, Armand J-P, Chabot GG, da Costa L, de Forni M (1993) CPT-11-induced cholinergic effects in cancer patients. J Clin Oncol 11:196–197

    CAS  PubMed  Google Scholar 

  8. Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ (1994) Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54:3723–3725

    CAS  PubMed  Google Scholar 

  9. Gupta E, Wang X, Ramirez J, Ratain MJ (1997) Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital. Cancer Chemother Pharmacol 39:40–444

    Article  Google Scholar 

  10. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramírez J, Rudin CM, Vokes EE, Ratain MJ (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388

    Article  CAS  PubMed  Google Scholar 

  11. Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ (1998) Genitic Predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847–854

    Article  CAS  PubMed  Google Scholar 

  12. Kaneda N, Yokokura T (1990) Nonlinear pharmacokinetics of CPT-11 in rats. Cancer Res 50:1721–1725

    CAS  PubMed  Google Scholar 

  13. Kawato Y, Tsumori T, Akahane K, Sekiguchi M, Sato K (1990) Inhibitory effect of CPT-11, a derivative of camptothecin, on acetylcholinesterase, and its binding ability to acetylcholine receptors (in Japanese). Clin Rep 24:7407–7412

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Kehrer DFS, Sparreboom A, Verweij J, de Bruijn P, Nierop CA, van de Schraaf J, Ruijgrok EJ, de Jonge MJA (2001) Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 7:1136–1141

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Kunimoto T, Nitta K, Tanaka T, Uehara M, Baba H, Takeuchi M, Yokokura T, Sawada S, Miyasaka T, Mutai M (1987) Antitumor activity of 7-ethyl-10-(4-(1-piperidino)-1-piperidino) carbonyloxycamptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 47:5944–5947

    CAS  PubMed  Google Scholar 

  19. Kurita A, Kaneda N (1999) High-performance liquid chromatographic method for the simultaneous determination of the camptothecin derivative irinotecan hydrochloride, CPT-11, and its metabolites SN-38 and SN-38 glucuronide in rat plasma with a fully automated on-line solid phase extraction system, PROSPEKT. J Chromatogr B 724:335–344

    Article  CAS  Google Scholar 

  20. Luo FR, Paranjpe PV, Guo A, Rubin E, Sinko P (2002) Intestinal transport of irinotecan in Caco-2 cells and MDCK II cells overexpressing efflux transporters Pgp, cMOAT, and MRP1. Drug Metab Dispos 30:763–770

    Article  CAS  PubMed  Google Scholar 

  21. Mehta VK, Cho C, Ford JM, Jambalos C, Poen J, Koong A, Lin A, Bastidas JA, Young H, Dunphy EP, Fisher G (2003) Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer. Int J Radiat Oncol Biol Phys 55:132–137

    Article  PubMed  Google Scholar 

  22. Ohe Y, Sakai Y, Shinkai T, Eguchi K, Tamura T, Kojima A, Kunikane H, Okamoto H, Karato A, Ohmatsu H, Kanzawa F, Saijo N (1993) Phase I study and pharmacokinetics of CPT-11 with 5-day continuous infusion. J Natl Cancer Inst 84:972–974

    Google Scholar 

  23. Ohno R, Okada K, Masaoka T, Kuramoto A, Arima T, Yoshida Y, Ariyoshi H, Ichimaru M, Sakai Y, Oguro M, Ito Y, Morishima Y, Yokomaru S, Ohta K (1990) An early II phase study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma. J Clin Oncol 8:1907–1912

    CAS  PubMed  Google Scholar 

  24. Onoue M, Kurita A, Kado S, Matsumoto T, Kaneda N, Uchida K, Kato I, Yokokura T (2008) Involvement of UDP-glucuronosyltransferase activity in Irinotecan-induced delayed-onset diarrhea in rats. Cancer Chemother Pharmacol 61:595–605

    Article  CAS  PubMed  Google Scholar 

  25. Rothenberg ML, Kuhn JG, Burris HA III, Morales MT, Nelson J, Eckardt JR, Rock MK, Terada K, von Hoff DD (1992) Phase I and pharmacokinetic trial of CPT-11 in patients with refractory solid tumors. Proc Am Soc Clin Oncol 11:2194–2204

    Google Scholar 

  26. Saliba F, Hagipantelli R, Misset J-L, Bastian G, Vassal G, Bonnay M, Herait P, Cote C, Mahjoubi M, Mignard D, Cvitkovic E (1998) Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment. J Clin Oncol 16:2745–2751

    CAS  PubMed  Google Scholar 

  27. Schmittel A, Jahnke K, Thiel E, Keiholz U (2004) Neomycin as secondary prophylaxis for irinotecan-induced diarrhea. Ann Oncol 15:1296

    Article  CAS  PubMed  Google Scholar 

  28. Shelby MK, Klassen CD (2006) Induction of rat UDP-glucuronosyltransferases in liver and duodenum by microsomal enzyme inducers that activate various transcriptional pathways. Drug Metab Dispos 34:1772–1778

    Article  CAS  PubMed  Google Scholar 

  29. Shimada Y, Yoshino M, Wakui A, Nakao I, Futatsuki K, Sakata Y, Kambe M, Taguchi T, Ogawa N (1993) Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol 11:909–913

    CAS  PubMed  Google Scholar 

  30. Shirao K, Shimada Y, Kondo H, Saito D, Yamao T, Ono H, Yokoyama T, Fukuda H, Oka M, Watanabe Y, Ohtsu A, Boku N, Fujii T, Oda Y, Muro K, Yoshida S (1997) Phase I-II study of irinotecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. J Clin Oncol 15:921–927

    CAS  PubMed  Google Scholar 

  31. Takasuna K, Kasai Y, Kitano Y, Mori K, Kobayashi R, Hagiwara T, Kakihata K, Hirohashi M, Nomura M, Nagai E, Kamataki T (1995) Protective effects of Kampo medicine and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats. Jpn J Cancer Res 86:978–984

    CAS  PubMed  Google Scholar 

  32. Takasuna K, Hasegawa T, Hirohashi M, Kato M, Nomura M, Nagai E, Yokoi T, Kamataki T (1996) Involvement of β-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride. Cancer Res 56:3752–3757

    CAS  PubMed  Google Scholar 

  33. Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E, Yokoi T, Kamataki T (1998) 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

    Article  CAS  PubMed  Google Scholar 

  34. Takeuchi S, Dobashi K, Fujimoto S, Tanaka K, Suzuki M, Terashima Y, Hasumi K, Akiya K, Negishi Y, Tamiya T, Tanizawa O, Sugawa T, Umesaki N, Sekiba K, Aono T, Nakano H, Noda K, Shirota M, Yakushiji M, Sugiyama T, Hashimoto M, Yajima A, Takamizawa H, Sonoda T, Takeda Y, Tomoda Y, Ohta M, Ozaki M, Hirabayashi K, Hiura M, Hatae M, Nishigaki K, Taguchi T (1991) A late phase II study of CPT-11 on uterine cervical cancer and ovarian cancer. Research groups of CPT-11 in Gynecologic Cancers (in Japanese). Jpn J Cancer Chemother 18:1681–1689

    CAS  Google Scholar 

  35. Van Leeuwen PAM, Drukker J, van der Kleyn NM, van den Boogaard AEJM, Soeters PB (1986) Morphological effects of high dose neomycin sulphate on the small and large intestine. Acta Morphol Neerl-Scand 24:223–234

    PubMed  Google Scholar 

  36. Von der Logt EMJ, Roelofs HMJ, Nagengast FM, Peters WHM (2003) Induction of rat hepatic and intestinal UDP-glucuronosyltransferases by naturally occurring dietary anticarcinogens. Carcinogenesis 24:1651–1656

    Article  Google Scholar 

Download references

Acknowledgments

We thank Tatsumi Mizutani, Kenji Kojima, Tsuyoshi Nagata, Yuriko Nagata, Ikuyo Makino, Takashi Sasaki, Yuichi Hara, Kazuhiko Yoshizawa, and Minoru Ando for their excellent technical assistance.

Author information

Authors and Affiliations

  1. Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi-shi, Tokyo, 186-8650, Japan

    Akinobu Kurita, Shoichi Kado, Tsuneo Matsumoto, Naoyuki Asakawa, Norimasa Kaneda, Ikuo Kato, Kazumi Uchida, Masaharu Onoue & Teruo Yokokura

Authors
  1. Akinobu Kurita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shoichi Kado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tsuneo Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naoyuki Asakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norimasa Kaneda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ikuo Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazumi Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masaharu Onoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Teruo Yokokura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akinobu Kurita.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kurita, A., Kado, S., Matsumoto, T. et al. Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of β-glucuronidase activity in intestinal lumen. Cancer Chemother Pharmacol 67, 201–213 (2011). https://doi.org/10.1007/s00280-010-1310-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-010-1310-4

Keywords

Search

Navigation