Toxicity of irinotecan (CPT-11) and hepato-renal dysfunction.
Various clinical and laboratory parameters have been investigated for their ability to predict toxicity arising from the use of the anticancer drug, irinotecan (CPT-11). In particular, patients deficient in the conjugation of SN-38, a metabolite of CPT-11, are known to be at greater risk. We describe one case of a patient with metastatic colorectal cancer treated with a single dose of CPT-11 at 125 mg/m(2). Although this patient lacked any known predictive factors for toxicity, he experienced severe side-effects several days later. We hypothesized that the toxicity in this patient was due to compromised SN-38 conjugation. Plasma samples were analyzed by reversed-phase high-performance liquid chromatography assay for CPT-11 and its metabolites at 96, 144, 168, 192 and 288 h post-administration. We observed that the concentrations of both the parent drug and its metabolites were markedly raised (11- to 60-fold expected). Additionally the estimated terminal half-lives were 1.5-7 times those expected (29.5, 101, 39.6 and 41.8 h for CPT-11, APC, SN-38G and SN-38, respectively). We conclude that the toxicity in this patient was not caused by deficient SN-38 conjugation, but by decreased drug excretion through both hepatic and renal routes.
Ong
S Y
SY
Medical Oncology, Sydney Cancer Centre, Missenden Road, Camperdown, NSW 2050, Australia.
Clarke
S J
SJ
Bishop
J
J
Dodds
H M
HM
Rivory
L P
LP
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D002430:Cecal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D000077146:Irinotecan; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008107:Liver Diseases / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008297:Male; D008875:Middle Aged; D059004:Topoisomerase I Inhibitors
D025601:Adenomatous Polyposis Coli Protein; D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin