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Intravenous Administration of Irinotecan Elevates the Blood ß-Glucuronidase Activity in Rats

Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo 186 [N. K., A. K., Y. H., T. Y.], and School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-03 [S. A.], Japan

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 regarding biliary excretion and deconjugation of SN-38 glucuronide by the enzyme ß-glucuronidase (ß-GL) in intestinal microflora. Prompted by the enzymological and structural similarity of CPT-11 to organophosphorus and carbamate insecticides, we studied the effect of CPT-11 on blood ß-GL activity in rats. The i.v. injection of CPT-11 in rats significantly elevated their plasma ß-GL activity (with phenolphthalein glucuronide as a substrate) at doses of 10 and 40 mg/kg, with peak activity observed 2–3 h after administration. SN-38 lactone and carboxylate had no effect on the plasma ß-GL level. The enhancement of the activity was also observed in serum using SN-38 glucuronide as a substrate. The serum ß-GL levels showed a close correlation between these substrates. The enhancement of plasma (serum) ß-GL activity is suggested to be a result of the release of ß-GL from liver microsomes. Serum and microsomal carboxylesterase were not significantly affected by CPT-11 administration.

¹ To whom requests for reprints should be addressed, at Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi, Tokyo 186, Japan.

Received 5/28/97. Accepted 9/26/97.

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