Influence of anticonvulsants on the metabolism and elimination of irinotecan. A North American Brain Tumor Consortium preliminary report.
The hepatic metabolism and biliary secretion of irinotecan (CPT-11, Camptosar) and metabolites is complex and involves cytochrome P450 isoenzymes, carboxylesterases, glucuronosyltransferase, and the ATP-dependent export pumps MRP-2 and MXR. Enzyme-inducing antiepileptic drugs (EIAEDs) such as phenytoin and carbamazepine are known to induce several of the metabolic pathways relevant to ininotecan 's elimination. The North American Brain Tumor Consortium phase I study is designed to determine the maximum tolerated dose and pharmacokinetics of irinotecan given every 3 weeks to patients who are receiving EIAEDs. The EIAEDs have altered both the pharmacokinetics and pharmacodynamics of irinotecan. Peak concentrations and the area under the plasma-time curves for both irinotecan and SN-38 were significantly decreased in patients receiving EIAEDs. The recommended phase II dose of irinotecan administered every 3 weeks is 750 mg/m2 for patients who have been receiving stable doses of EIAEDs.
Kuhn
John G
JG
kuhn@uthscsa.edu
D000927:Anticonvulsants / Q000008:administration & dosage*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D000089762:Multidrug Resistance-Associated Protein 2; D010672:Phenytoin / Q000008:administration & dosage; D011336:Probability; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome
C000715087:ABCC2 protein, human; D000927:Anticonvulsants; D000972:Antineoplastic Agents, Phytogenic; D000089762:Multidrug Resistance-Associated Protein 2; D002220:Carbamazepine; D010672:Phenytoin; D000077146:Irinotecan; D002166:Camptothecin