Chronopharmacokinetics Of Erlotinib And Circadian Rhythms Of Related Metabolic Enzymes In Lewis Tumor-bearing Mice

ObjectiveThe purpose of the current study was to investigate the effect of the dosing time on the pharmacokinetics of erlotinib and the circadian rhythms of the metabolism enzymes that are responsible for the metabolism of erlotinib in tumor-bearing mice.Methods1.Female C57BL mice were contained under standardized12h light/dark circadian conditions (7:00-19:00was light phase, and19:00-7:00was dark phase) for3weeks and randomly assigned into six groups.2.Erlotinib hydrochloride was orally administrated to the mice in each group at8:00,12:00,16:00,20:00,24:00and4:00, respectively. Blood was drawn from the eyeballs of the mice at5,10,20,30,45min,1.5,3,5,8,12,16and24h after each administration. All the mice were sacrificed immediately after their blood was taken and the liver of them were kept for further research.3.The plasma concentration of erlotinib was determined through a high-performance liquid-chromatographic (HPLC) assay and the parameters were calculated by WinNonlin.4.The mice were sacrificed and the total mRNA was extracted from liver tissues to determine the expression of the mRNA of the related drug metabolism enzymes by qRT-PCR.Results1. The AUC and MRT of these groups were of apparent difference. AUCo-24h and MRTo-24h were the lowest in the20:00administration group as compared to other groups. Tmax of the20:00,24:00and4:00groups was apparently higher than that of the morning groups. CL showed significant difference in all groups, with the highest in the20:00group. CL of the day groups was lower than that of the night groups. Cmax was the highest in the12:00group and the lowest in the20:00group.2. The mRNA levels of Cyp3all, Cyp3al3, Cypla2, which are responsible for metabolizing erlotinib displayed significant variations over the period of24hours. The expressions of these enzymes were generally higher during12:00-16:00and the dark phase than that of4:00-8:00.Conclusion These results indicates that circadian rhythm plays a critical role in pharmacokinetics of erlotinib in mice and the mechanisms may be partly attributed to the gene expression rhythms of drug metabolizing enzymes in liver tissues.