Influence of phenytoin on the disposition of irinotecan: a case report.
Irinotecan (CPT-11), a water-soluble topoisomerase I inhibitor, is metabolized by carboxylesterase enzymes to form an active metabolite, SN-38. Recent studies have shown that irinotecan also undergoes oxidative metabolism by the P450 isozyme CYP3A4, leading to the formation of a minor inactive metabolite, 7-ethyl-10-[4-N-[(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). The elucidation of this metabolic pathway suggests the potential for drug interactions when irinotecan is administered with other inducers or substrates of CYP3A4. In this report, the authors summarize the pharmacokinetic profile of irinotecan and its major metabolites with and without concomitant phenytoin administration in an individual patient. These studies revealed that concomitant phenytoin administration resulted in a marked decrease in the systemic exposure to irinotecan and SN-38 and an increase in the exposure to APC. The area under the curve of irinotecan and SN-38 decreased by 63% and 60%, respectively; the area under the curve of APC increased by approximately 16%. Further detailed pharmacokinetic studies of irinotecan in patients receiving concomitant therapy with enzyme-inducing anticonvulsants are required so that rational dosing recommendations can be provided for this patient population.
Murry
Daryl J
DJ
Texas Children's Cancer Center/Baylor College of Medicine, Houston, USA.
Cherrick
Irene
I
Salama
Veronia
V
Berg
Stacey
S
Bernstein
Mark
M
Kuttesch
Nancy
N
Blaney
Susan M
SM
D000293:Adolescent; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D002166:Camptothecin / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics; D018450:Disease Progression; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D017294:Ondansetron / Q000627:therapeutic use; D010634:Phenobarbital / Q000627:therapeutic use; D010672:Phenytoin / Q000493:pharmacokinetics* / Q000494:pharmacology; D010870:Pineal Gland; D010871:Pinealoma / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D011355:Prodrugs / Q000493:pharmacokinetics*; D016879:Salvage Therapy; D012640:Seizures / Q000150:complications / Q000188:drug therapy
D000927:Anticonvulsants; D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; C100720:RPR 121056; D017294:Ondansetron; D010672:Phenytoin; D005047:Etoposide; D000077146:Irinotecan; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D016190:Carboplatin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002945:Cisplatin; D008558:Melphalan; D002166:Camptothecin; D010634:Phenobarbital