INTRAVENOUS ADMINISTRATION OF IRINOTECAN ELEVATES THE BLOOD BETA-GLUCURONIDASE ACTIVITY IN RATS

7-Ethyl-10-hydroxycamptothecin (SN-38) is the active metabolite of an anticancer drug, irinotecan (CPT-11), Severe late diarrhea is the dose -limiting toxic effect of CPT-11, This diarrhea has been examined rega rding biliary excretion and deconjugation of SN-38 glucuronide by the enzyme beta-glucuronidase (beta-GL) in intestinal microflora. Prompted by the enzymological and structural similarity of CPT-11 to organopho sphorus and carbamate insecticides, we studied the effect of CPT-11 on blood beta-GL activity in rats. The i.v. injection of CPT-11 in rats significantly elevated their plasma beta-GL activity (with phenolphtha lein glucuronide as a substrate) at doses of 10 and 40 mg/kg, with pea k activity observed 2-3 h after administration, SN-38 lactone and carb oxylate had no effect on the plasma beta-GL level, The enhancement of the activity was also observed in serum using SN-38 glucuronide as a s ubstrate. The serum beta-GL levels showed a close correlation between these substrates, The enhancement of plasma (serum) beta-GL activity i s suggested to be a result of the release of beta-GL from liver micros omes, Serum and microsomal carboxylesterase were not significantly aff ected by CPT-11 administration.