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

Publication date: Available online 1 November 2018Source: Pharmacological ResearchAuthor(s): Kai-Wen Cheng, Chih-Hua Tseng, Cherng-Chyi Tzeng, Yu-Lin Leu, Ta-Chun Cheng, Jaw-Yuan Wang, Jia-Ming Chang, Yun-Chi Lu, Chiu-Min Cheng, I-Ju Chen, Yi-An Cheng, Yeh-Long Chen, Tian-Lu ChengAbstractIrinotecan (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 β-glucuronidase (βG) to be SN-38, thus leading to intestinal toxicity. Thus, inhibition of the intestinal bacterial βG 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 βG (eβG)-specific inhibitor pyrazolo[4,3-c]quinoline derivative (TCH-3562) for potential use in tumor therapy. TCH-3562 exhibited efficacious inhibitory potency of endogenous βG activity in two anaerobes, Eubacterium sp. and Peptostreptococcus anaerobius. Oral administration of TCH-3562 also effectively reduced the bacterial βG activity in mice intestine. Moreover, pharmacokinetic analysis of TCH-3562 revealed a relatively ...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research