Pharmacological inhibition of bacterial ß-glucuronidase prevents irinotecan-induced diarrhea without impairing its antitumor efficacy in vivo.
Pharmacol Res
; 139: 41-49, 2019 01.
Article
in En
| MEDLINE
| ID: mdl-30391354
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 ß-glucuronidase (ßG) to be SN-38, thus leading to intestinal toxicity. Thus, inhibition of the intestinal bacterial ßG 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 ßG (eßG)-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 ßG activity in two anaerobes, Eubacteriumsp. and Peptostreptococcus anaerobius. Oral administration of TCH-3562 also effectively reduced the bacterial ßG 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 ßG 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Quinolines
/
Bacterial Proteins
/
Colonic Neoplasms
/
Diarrhea
/
Irinotecan
/
Glucuronidase
/
Antineoplastic Agents, Phytogenic
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Pharmacol Res
Journal subject:
FARMACOLOGIA
Year:
2019
Document type:
Article
Affiliation country:
Taiwan