Relationship between development of diarrhea and the concentration of SN-38, an active metabolite of CPT-11, in the intestine and the blood plasma of athymic mice following intraperitoneal administration of CPT-11.

Severe diarrhea occurred during daily intraperitoneal administration of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) at a dose of 50 mg/kg in athymic mouse. Serial determination of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38), with the use of an on-line solid extraction HPLC system, demonstrated that much higher levels of the compounds are retained in the intestine and the blood plasma after five consecutive daily injections than after a single injection. Histologic examination of the gastrointestinal tract showed hemorrhagic colitis on day 7 and later after five consecutive daily injections of CPT-11. The direct cause of diarrhea associated with CPT-11 administration is considered to be enterocolitis caused by high levels of SN-38 and/or CPT-11 retained for a long period in the intestine.