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.

Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism

“…Studies indicated that atropaldehyde resulted in an accumulation of reactive species and toxicity by inhibiting the detoxifying enzymes glutathione S-transferase and aldehyde dehydrogenase [16]. The metabolism of GEF has been extensively investigated in vitro and in vivo [17][18][19][20]. Most of GEF was metabolized in liver and mainly excreted in feces, less than 7% in the urine, irrespective of dose route or species.…”

“…However, studies on the bioactivation of GEF are limited. To date, only glutathione-adducts were unraveled in microsomes and hepatocytes [20,23].…”

Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers

“…The removal of the morpholine ring structure, as observed for the formation of metabolite M2, is well-established for mammalian biotransformation of related alkylmorpholine-structures [14, 15], although sometimes without the extensive oxidation of the remaining alkoxy-chain observed for copanlisib, leading to M2 and finally resulting in M4. However, apparently there are significant differences between species and between in vitro and in vivo findings regarding the extent of oxidative degradation of morpholine structures, as described, e.g., for gefitinib, which undergoes oxidation of the alkoxy side-chain only in vitro, while in vivo in man only oxidation products of the morpholine with ring opening are described [16–18]. …”

Microbioreactors and Perfusion Bioreactors for Microbial and Mammalian Cell Culture

“…Organ-on-a-chip [17] is an ongoing research to hasten the process of drug discovery and development. In vitro drug screening and safety testing [18][19][20] are essential to minimize extensive studies on laboratory animals. Microbioreactors designed as per the need of the study will be highly beneficial to understand the potency and toxicity of the developed drug molecules.…”