Résumé
OBJECTIVE To investigate the effect of the dosing time on the pharmacokinetics of gefitinib and its potential mechanism. METHODS Female BALB/c nude mice were housed under standardized 12 h light/dark circadian conditions(light on at 7:00,off at 19:00)for two weeks before a non-small cell lung cancer(NSCLC)model was established. Two weeks later,they were divided into 2 groups(8:00,20:00)randomly. Gefitinib was orally administered at the dose of 1 mg · kg-1 to the mice in each group at 8:00 or 20:00,respectively. Blood was collected at 10 different time points after each administration. Livers were collected every 4 h during the 24 h period from the non-administrated nude mice of NSCLC model. The plasma concentration of gefitinib was determined through an HPLC-MS/MS and the parameters were calculated by WinNonlin 6.3. The total RNA was extracted from livers,purified, synthesized to cDNA that was subjected to qRT-PCR analysis for mRNA expression levels of cyto?chrome P450 enzymes(Cyp)3a11,Cyp3a13,pregnane X receptor(PXR)and constitutive androstane receptor (CAR). RESULTS The area under the plasma concentration-time curve (AUC) and mean residence time (MRT) of 8:00 administration group were higher than those of 20:00 administration group(P<0.05). The clearance(Clz/F) of 8:00 administration group was lower than that of 20:00 administration group(P<0.05). The mRNA expression levels of PXR and CAR were consistent with those of Cyp3a11 and Cyp3a13. CONCLUSION Circadian rhythm exists in the pharmacokinetics of gefitinib and it may be closely related to CYP3A and its regulator genes.
Résumé
Biomarkers of non-small cell lung cancer(NSCLC)can facilitate an efficient diagnosis, improve therapeutic effects,reduce the side effects of other treatments,ameliorate prognosis and predict relapse of the disease and drug resistance. This paper summarized the biomarkers which were newly discovered and their functions in clinical practices in order to guide individualized treatment and help adjust treatment. The exploration of biomarkers of NSCLC will become a priority in future research.