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| 標題: | Pharmacological inhibition of bacterial beta-glucuronidase prevents irinotecan-induced diarrhea without impairing its antitumor efficacy in vivo |
| 作者: | 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 |
| 貢獻者: | 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 |
| 關鍵字: | Irinotecan (CPT-11)
Glucuronidation
Bacterial beta-glucuronidase
Chemotherapy-induced diarrhea
beta-Glucuronidase inhibitor
Pyrazolo[4,3-c]quinolines |
| 日期: | 2019-01 |
| 上傳時間: | 2020-07-29 13:51:50 (UTC+8) |
| 出版者: | ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD |
| 摘要: | 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. |
| 關聯: | Pharmacological Research, v.139, pp.41-49 |
| 顯示於類別: | [藥學系(所)] 期刊論文
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