厄洛替尼在荷瘤小鼠的时辰药代动力学特点

Chronopharmacokinetics of erlotinib in tumor-bearing 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C57BL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0.5 mL,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。

OBJECTIVE To investigate the effect of the dosing time on the pharmacokinetics of erlotinib. METHODS Female C57BL mice were contained under standardized 12h light /dark circadian conditions（ lights on at 7： 00,off at 19： 00） for 3 weeks and randomly assigned into six groups. Erlotinib hydrochloride was orally administrated to the mice in each group at 8： 00,12： 00,16： 00,20： 00,24： 00 and 4： 00,respectively. Blood was drawn from the eyeballs of the mice at 12 different time points after each administration. The plasma concentration of erlotinib was determined through a high-performance liquid-chromatographic assay and the parameters were calculated by WinNonlin. RESULTS The area under curre（ AUC） and mean residence time（ MRT） of these groups were apparently different. AUC0 ～ 24 hand MRT0 ～ 24 hwere the lowest in the 20： 00 administration group as compared to other groups（ P〈0. 01）. Tmaxof the 20： 00,24： 00 and 4： 00 groups was apparently higher than that of the 8： 00 and 12： 00 groups（ P〈0. 01）. The clearance of the light phase groups was lower than that of the dark phase groups（ P〈0. 01）,with the highest in the 20： 00 group. The peak value of cmaxappeared in the 12： 00 group and the lowest in the 20： 00 group（ P〈0. 01）. CONCLUSION Circadian rhythm plays a critical role in pharmacokinetics of erlotinib in mice.