Glucuronidation with Diarrhea Metabolic Fate of Irinotecan in Humans: Correlation of Updated Version

hinotecan (7.ethyl-1O.[4-(1.piperidino)-1-piperidlnolcarbonyloxy. camptothecin (CPT-11) Is hydrolyzed by the enzyme carboxyl esterase to 7-ethyl-lO-hydroxycamptothecin (SN-38), which further undergoes glucu ronic acid conjugation to form the corresponding SN.38 glucuronide (SN-38G). SN-38 is believed to be the cause oftreatment-related diarrhea, a dose-limiting tOxiCityof CPT-1l observed in phase I clinical trials This study investigated the effect of glucuronidation on the concentrations of SN-38 following CPT-11 Infusion In 21 patIents undergoing a phase I triaL To assess the relationship between gastrointestinal tOXiCItYand pharma cokinetics of CFr-11 and its metabolites, we defined a “biliary index― of SN-38 which was the product ofthe relative area ratio ofSN-38 to SN-38G and the total CPT-11 area under the plasma concentration-time curve. Nine patients with grade 3-4 diarrhea had higher biliary Indexes than 12 patients with grade 0—2diarrhea (median 2228 versus 5499, P 0.0004). The relatively higher index values, suggestive of higher billary concentra tions of SN-38, were possibly due to low glucuronidation rate& Hence, modulation of glucuronidatlon may be effective in Increasing the thera peutic index of CPT-11.