Background Gefitinib is an orally active, selective EGFR TKI used in the treatment of patients with advanced NSCLC carrying activating EGFR mutations. In fact, it is well established that gefitinib is more active in some patient subgroups, such as Asians, females, never smokers and adenocarci noma histotypes which have a higher probability of har bouring activating mutations http://www.selleckchem.com/products/Enzastaurin.html in the tyrosine kinase domain, the most frequent being L858R in exon 21 and Del in exon 19. As a consequence most of the NSCLCs containing wild type EGFR receptor are excluded and hence the role of gefitinib for the treatment of NSCLC is limited. However, some studies have shown that patients without mutations responded to gefitinib with response rates reaching 6. 6%.

In addition to can cer cell genomic determinants of sensitivity, some pharma cokinetic parameters may also play a role in the variable response to gefitinib and other TKIs. When administered at 250 mg/day, gefitinib is 60% orally absorbed and 90% plasma protein bound. The very high distribution volume of gefitinib clearly indicates that the drug is extensively distributed in tissues Inhibitors,Modulators,Libraries such as liver, kidney, gastrointestinal tract, lung and in tumors. A tendency to accumulate in the Inhibitors,Modulators,Libraries lung was observed with concentrations 10 times higher Inhibitors,Modulators,Libraries than in plasma. We have recently demonstrated in NSCLC cell Inhibitors,Modulators,Libraries lines that the uptake of gefitinib is an essentially active process leading to intracellular gefitinib concentrations more than two hundred times higher than outside the cells. There are few data on gefitinib intracellular metabolism in tumors, the majority of the available data concerns liver metabolism.

In vitro and in vivo studies indicate that in the liver Inhibitors,Modulators,Libraries gefitinib is mainly metabolized by cytochrome P450 dependent activities, including CYP3A4, CYP3A5 and CYP2D6. The main metabolic path way characterized by using human liver microsomes include morpholine ring opening, O demethylation of the methoxy substituent on the quinazoline ring structure and oxidative defluorination of the halogenated phenyl group. A study investigating the contribution of individual CYPs to gefitinib metabolism demonstrated that gefitinib disappeared with similar clearance when incubated with CYP3A4 or CYP2D6 enzymes, less efficiently with CYP3A5 or CYP1A1, whereas CYP1A2 and CYP1B1 were not involved in the metabolism of the drug.

Incuba tion with CYP3A4 and to a lesser extent CYP3A5, pro duced a similar range of metabolites as that produced by liver microsomes, but the main plasma metabolite, the O desmethyl derivative present at plasma concentra tions similar to gefitinib, was formed predominantly through the CYP2D6 enzyme. CYP1A1 is one of the three members of the CYP1 family mainly expressed in extra hepatic selleck chemicals Ruxolitinib tissue, involved in the metabolism of a large number of xenobiotics as well as a small number of endogenous substrates.