Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea.

TLDR

Irinotecan is metabolized to SN‑38, which is glucuronidated to SN‑38G; SN‑38 is believed to cause the dose‑limiting diarrhea observed in clinical trials. The study examined how glucuronidation affects SN‑38 plasma concentrations during CPT‑11 infusion in 21 phase‑I patients. Researchers calculated a biliary index—product of the SN‑38/SN‑38G area ratio and total CPT‑11 AUC—to link gastrointestinal toxicity with drug pharmacokinetics. Patients with grade 3‑4 diarrhea had markedly higher biliary indexes, indicating lower glucuronidation rates, and suggest that enhancing glucuronidation could widen CPT‑11’s therapeutic window.

Abstract

Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptotheci n (CPT-11) is hydrolyzed by the enzyme carboxyl esterase to 7-ethyl-10-hydroxycamptothecin (SN-38), which further undergoes glucuronic acid conjugation to form the corresponding SN-38 glucuronide (SN-38G). SN-38 is believed to be the cause of treatment-related diarrhea, a dose-limiting toxicity of CPT-11 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 toxicity and pharmacokinetics of CPT-11 and its metabolites, we defined a "biliary index" of SN-38 which was the product of the relative area ratio of SN-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 0-2 diarrhea (median 2228 versus 5499, P = 0.0004). The relatively higher index values, suggestive of higher biliary concentrations of SN-38, were possibly due to low glucuronidation rates. Hence, modulation of glucuronidation may be effective in increasing the therapeutic index of CPT-11.