厄洛替尼在荷瘤小鼠的时辰药代动力学特点

摘要

OBJECTIVE To investigate the effect of the dosing time on the pharmacokinetics oferlotinib.METHODS Female C57BL mice were contained under standardized 12h light/dark circadianconditions (lights on at 7:00,off at 19:00)for 3 weeks and randomly assigned into six groups.Erlotinibhydrochloride was orally administrated to the mice in each group at 8:00,12:00,16:00,20:00,24:00and 4:00,respectively.Blood was drawn from the eyeballs of the mice at 12 different time points aftereach administration.The plasma concentration of erlotinib was determined through a high-performanceliquid-chromatographic assay and the parameters were calculated by WinNonlin. RESULTSThe area under curre (AUC)and mean residence time (MRT)of these groups were apparently differ-ent.AUC0 ~24 h and MRT0 ~24 h were the lowest in the 20:00 administration group as compared to othergroups (P<0.01 ).Tmax of the 20:00,24:00 and 4:00 groups was apparently higher than that of the8:00 and 12:00 groups (P<0.01 ).The clearance of the light phase groups was lower than that of thedark phase groups (P<0.01 ),with the highest in the 20:00 group.The peak value of cmax appeared inthe 12:00 group and the lowest in the 20:00 group (P<0.01 ).CONCLUSION Circadian rhythm playsa critical role in pharmacokinetics of erlotinib in mice.%目的：探讨厄洛替尼时辰给药的药代动力学特点。方法将雌性荷瘤C57 BL小鼠于严格人工昼夜（7：00～19：00为明期；19：00～次日7：00为暗期）条件下适应性饲养3周，按照分组分别在8：00，12：00，16：00，20：00，24：00以及4：00 ig给予厄洛替尼150 mg·kg -1。于给药后选取12个时间点采集各组血样0．5mL，采用HPLC测定血药浓度，应用WinNonlin软件计算各组药动学参数。结果6个时间点组之间的曲线下面积（AUC）和平均滞留时间（MRT）均有显著性差异（P＜0．01），其中20：00给药组、24：00给药组的AUC0～24 h和MRT0～24 h明显小于其他时间点给药组。20：00，24：00以及4：00给药组的的Tmax明显小于8：00，12：00和16：00给药组，差别有统计学意义（P＜0．01）。6个时间点给药组的清除率（Cl）之间有显著性差异（P＜0．01），其中20：00给药组最高，且暗期各组均较明期各组Cl高。12：00给药组的cmax最高，而20：00给药组的cmax最低，两组之间差异有统计学意义（P＜0．01）。结论厄洛替尼在荷瘤小鼠药动过程具有时辰节律性特点。