Chronopharmacokinetics of gefitinib and its mechanisms in tumor-bearing nude mice / 中国药理学与毒理学杂志

ABSTRACT

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 700,off at 1900)for two weeks before a non-small cell lung cancer(NSCLC)model was established. Two weeks later,they were divided into 2 groups(800,2000)randomly. Gefitinib was orally administered at the dose of 1 mg · kg-1 to the mice in each group at 800 or 2000,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 800 administration group were higher than those of 2000 administration group(P<0.05). The clearance(Clz/F) of 800 administration group was lower than that of 2000 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.