Pharmacological inhibition of bacterial beta-glucuronidase prevents irinotecan-induced diarrhea without impairing its antitumor efficacy in vivo

doi:10.1016/j.phrs.2018.10.029

CNU IR > Pharmacy and Science > Dept. of Pharmacy > Periodical Articles > Item 310902800/32606

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Title:	Pharmacological inhibition of bacterial beta-glucuronidase prevents irinotecan-induced diarrhea without impairing its antitumor efficacy in vivo
Authors:	Cheng, Kai-Wen Tseng, Chih-Hua Tzeng, Cherng-Chyi Leu, Yu-Lin Cheng, Ta-Chun Wang, Jaw-Yuan Chengm, Chiu-Min Yu-Lin Leu(呂玉玲) Cheng, Chiu-Min Chen, I-Ju Cheng, Yi-An Chen, Yeh-Long Cheng, Tian-Lu
Contributors:	Kaohsiung Med Univ, Ctr Biomarkers & Biotech Drugs Kaohsiung Med Univ, Sch Pharm Kaohsiung Med Univ, Dept Fragrance & Cosmet Sci Kaohsiung Med Univ, Ctr Infect Dis & Canc Res Kaohsiung Municipal Tatung Hosp, Dept Pharm Kaohsiung Med Univ, Dept Med & Appl Chem Chia Nan Univ Pharm & Sci, Dept Pharm Kaohsiung Med Univ, Grad Inst Clin Med, Coll Med Kaohsiung Med Univ Hosp, Div Gastroenterol & Gen Surg, Dept Surg Dev Ctr Biotechnol, Dept Anim Pharmacol Natl Res Program, Preclin Anim Pharmacol Testing Ctr Kaohsiung Med Univ, Grad Inst Med, Coll Med Natl Kaohsiung Univ Sci & Technol, Dept & Grad Inst Aquaculture Kaohsiung Med Univ, Dept Biomed & Environm Biol Natl Sun Yat Sen Univ, Inst Biomed Sci Kaohsiung Med Univ Hosp, Dept Med Res
Keywords:	Irinotecan (CPT-11) Glucuronidation Bacterial beta-glucuronidase Chemotherapy-induced diarrhea beta-Glucuronidase inhibitor Pyrazolo[4,3-c]quinolines
Date:	2019-01
Issue Date:	2020-07-29 13:51:50 (UTC+8)
Publisher:	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Abstract:	Irinotecan (CPT-11), a first-line chemotherapy for advanced colorectal cancer, causes serious diarrhea in patients receiving treatment. The underlying mechanism has been shown that the active metabolite of CPT-11, SN-38, is metabolized to the inactive metabolite SN-38 glucuronide (SN-38 G) during hepatic glucuronidation, and subsequently is exported into the intestine, where SN-38 G is hydrolyzed by bacterial beta-glucuronidase (beta G) to be SN-38, thus leading to intestinal toxicity. Thus, inhibition of the intestinal bacterial beta G activity is expected to prevent CPT-11-induced diarrhea. However, the effects of such inhibition on serum pharmacokinetics of SN-38, the key determinant of CPT-11 treatment, are uncertain. Here, we determined the effects of a potent E. coli beta G (e beta G)-specific inhibitor pyrazolo[4,3-c]quinoline derivative (TCH-3562) for the potential use in preventing CPT-11-induced diarrhea. TCH-3562 exhibited efficacious inhibitory potency of endogenous beta G activity in two anaerobes, Eubacteriumsp. and Peptostreptococcus anaerobius. Oral administration of TCH-3562 also effectively reduced the bacterial beta G activity in mice intestine. Moreover, pharmacokinetic analysis of TCH-3562 revealed a relatively low amount of TCH-3562 was detected in the plasma whereas the majority of TCH-3562 was found in the feces. Importantly, co-treatment of CPT-11 and TCH-3562 did not decrease active SN-38 level in mice plasma. Finally, we established that TCH-3562 as an adjuvant treatment showed protective effects on CPT-11 induced diarrhea and had no negative effects on the therapeutic efficacy of CPT-11 in tumor-bearing mice. Therefore, inhibition of the intestinal bacterial beta G activity by the specific inhibitor, TCH-3562, is promising to prevent CPT-11-induced diarrhea while maintaining its anti-tumor efficacy that may have clinical potentials for the treatment with CPT-11.
Relation:	Pharmacological Research, v.139, pp.41-49
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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