title: Metabolite characterization of anti-cancer agent gefitinib in human hepatocytes.
abstract: Intensive Biotransformation studies on Gefitinib could play a significant role in designing and synthesizing new drugs around the core structure of Gefitinib. These studies may be useful in developing an entirely new drug by blocking the metabolic spots in Gefitinib. Gefitinib (Iressa) was the first oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Gefitinib shows toxicity to cancer cells and has the capability to inhibit the growth of cancer cells. Gefitinib is considered as one of the selective EGFR inhibitors to be available in clinical practice. In 2003, FDA had approved Gefitinib for metastatic non-small-cell lung cancer therapy (NSCLC). However, it was observed that NSCLC Patients who responded to treatment developed resistance to Gefitinib. Hence, in the present study Gefitinib was incubated with hepatocytes to identify both phase-I and Phase-II metabolites. Identified Phase -I metabolites were due to oxidative defluorination, N-dealkylation and loss of morpholine ring. One of the phase-II metabolites identified i.e. the glutathione adduct suggests the need to modify the structure of the drug for higher potency and safety.
authors.forename: Prashant
authors.initials: P
authors.lastname: Surve
authors.forename: Selvan
authors.initials: S
authors.lastname: Ravindran
authors.forename: Arghya
authors.initials: A
authors.lastname: Acharjee
authors.forename: Himanshu
authors.initials: H
authors.lastname: Rastogi
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
authors.affiliation: Departments of Bio- Analytical and Biotransformation, Drug Metabolism and Pharmacokinetics Unit, Sai Life Sciences Limited, Building 1, Plot No 2, Chrysalis Enclave, International Biotech Park, Pune 411057, Maharashtra, India. selvan_ravindran@yahoo.com.
authors.forename: Pradnya
authors.initials: P
authors.lastname: Honrao
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003640:Dealkylation; D000077156:Gefitinib; D005978:Glutathione / Q000378:metabolism; D054879:Halogenation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D010084:Oxidation-Reduction; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D005978:Glutathione; D000077156:Gefitinib