Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man

Abstract

Following oral administration of [14C]-gefitinib to albino and pigmented rats, radioactivity was widely and rapidly distributed, with the highest levels being found in liver, kidney, lung and gastrointestinal tract, but with only low levels penetrating the brain. Levels of radioactivity persisted in melanin-containing tissues (pigmented eye and skin). Binding to plasma proteins was high (86-94%) across the range of species examined and was 91% in human plasma. Substantial binding occurred to both human serum albumin and alpha-1 acid glycoprotein. Following oral and intravenous administration of [14C]-gefitinib, excretion of radioactivity by rat, dog and human occurred predominantly via the bile into faeces, with < 7% of the dose being eliminated in urine. In all three species, gefitinib was cleared primarily by metabolism. In rat, morpholine ring oxidation was the major route of metabolism, leading to the formation of M537194 and M608236 as the main biliary metabolites. Morpholine ring oxidation, together with production of M523595 by O-demethylation of the quinazoline moiety, were the predominant pathways in dog, with oxidative defluorination also occurring to a lesser degree. Pathways in healthy human volunteers were similar to dog, with O-demethylation and morpholine ring oxidation representing the major routes of metabolism.

Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor

“…Gefitinib has a high volume of distribution in rats (8 -10 L/ kg), dogs (2 -6 L/kg), and cancer patients (1,400 L), which is consistent with pronounced distribution of gefitinib into tissues. This was confirmed by a rat tissue distribution study where gefitinib-related material was found extensively distributed, achieving tissue/blood ratios of >10 in a number of organs, including lung, liver, and kidney (16). Further work to examine distribution into an orthotopic rat lung model is also summarized, together with gefitinib human tumor concentrations generated in a breast cancer study (18), originally presented as a poster at the 40th American Society of Clinical Oncology Annual Meeting in New Orleans (June 2004).…”

“…Plasma and tumor extracts were also assayed for gefitinib and its major metabolites (M523595 and M537194) by HPLC with tandem mass spectrometric detection (HPLC-MS/MS). The distribution of radioactivity was also determined in a separate group of female nude mice (bearing LoVo tumor xenografts), which had received four daily oral doses of [ 14 C]-gefitinib at 50 mg/kg (incorporating 500 ACi/kg), by whole body autoradiography of individual mice at various times after the final dose, as described previously (16).…”

“…The distribution of radioactivity was determined by examination of individual rats at various times after the final dose by whole body autoradiography, as described previously (16).…”

“…Gefitinib is cleared primarily by metabolism in rat, dog, and human (16), with morpholine ring oxidation and Odemethylation of the quinazoline methoxy group being the main routes of metabolism. Desmethyl-gefitinib (M523595) is the predominant metabolite observed in human plasma and is present at concentrations similar to gefitinib (17,18).…”

Successful Treatment of Carcinomatous Meningitis with Gefitinib in a Patient with Lung Adenocarcinoma Harboring a Mutated EGF Receptor Gene

“…The low concentration of gefitinib in the CSF may be attributable to its low permeability at the blood-brain barrier, which affects the delivery of many drugs. It was previously demonstrated that the concentration of [ 14 C]-labeled gefitinib in normal rat brain and spinal cord was only 2% of that in lung, suggesting that gefitinib does not readily cross the bloodbrain barrier (McKillop et al 2004); however, the concentration of gefitinib in the CSF was not measured. Only one previous report considered the concentration of gefitinib in the CSF of NSCLC patients with leptomeningeal metastases (Jackman et al 2006).…”