Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea.
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.
Department of Medicine, University of Chicago Pritzker School of Medicine, Illinois 60637.
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E
Gupta
T M
TM
Lestingi
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R
Mick
J
J
Ramirez
E E
EE
Vokes
M J
MJ
Ratain
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D005965:Glucuronates / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan
D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D000077146:Irinotecan; D002166:Camptothecin