Lessons learned from the irinotecan metabolic pathway.
Irinotecan, a camptothecin analogue, is a prodrug which requires bioactivation to form the active metabolite SN-38. SN-38 acts as a DNA topoisomerase I poison. Irinotecan has been widely used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. However, large inter-patient variability in irinotecan and SN-38 disposition, as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan. Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy. Irinotecan is subjected to be shunted between CYP3A4 mediated oxidative metabolism to form two inactive metabolites APC or NPC and tissue carboxylesterase mediated hydrolysis to form SN-38 which is eventually detoxified via glucuronidation by UGT1A1 to form SN-38G. The pharmacology of this compound is further complicated by the existence of genetic inter-individual differences in activation and deactivation enzymes of irinotecan (e.g., CYP3A4, CYP3A5, UGT1A1) and sharing competitive elimination pathways with many concomitant medications, such as anticonvulsants, St. John's Wort, and ketoconazole. Efflux of the parent compound and metabolites out of cells by several drug transporters (e.g., Pgp, BCRP, MRP1, MRP2) also occurs. This review highlights the latest findings in drug activation, transport mechanisms, glucuronidation, and CYP3A-mediated drug-drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent.
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MK
Washington University School of Medicine, Department of Medicine, St Louis, MO 63110, USA.
McLeod
H L
HL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000633:toxicity; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003967:Diarrhea / Q000139:chemically induced; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D020719:Glucuronides; D000077146:Irinotecan; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin