Pharmacological inhibition of bacterial &bgr; glucuronidase prevents irinotecan induced diarrhea without impairing its antitumor efficacy in vivo
&NA; 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 &bgr; glucuronidase &bgr;G) to be SN 38, thus leading to intestinal toxicity. Thus, inhibition of the intestinal bacterial &bgr;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 &bgr;G (e&bgr;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 &bgr;G activity in two anaerobes, Eubacteriumsp. and Peptostreptococcus anaerobius. Oral administration of TCH 3562 also effectively reduced the bacterial &bgr;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 &bgr;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.
Pharmacological research