Effect Of Borneol And Quercetin On The Penetration Of Erlotinib Across The Blood-brain Barrier In Mice

Objective To observe the effect of borneol and quercetin on the penetration of erlotinib across the blood-brain barrier in mice.Methods 1.To devolop a UPLC-MS method to determine erlotinib and OSI-420 in mice plasma and brain.2. Experiments were performed on 20-25 g female KM mice. Mice were divided by five groups: Erlotinib(50 mg·kg-1) administration group; Erlotinib(50 mg·kg-1) + borneol(125 mg·kg-1) administration group; Erlotinib(50 mg·kg-1) + borneol(250 mg·kg-1) administration group; Erlotinib(50 mg·kg-1) + quercetin(25 mg·kg-1) administration group; Erlotinib(50 mg·kg-1)+ quercetin(50 mg·kg-1) administration group. Total blood and brain specimans were colleted at 15, 30, 60, 120, 240, 360, 480 min post-dose erlotinib. The concentrations of erlotinib and OSI-420 in plasma and brain tissues were determined by ultra performance liquid chromatography coupled with MS detection, and the pharmacokinetic parameters were calculated based on the pharmacokinetic software of DAS 3.23. And then,the character of penetrating blood-brain barrier through the result of the AUCtotal brain/AUCtotal blood was evaluated.Results 1. The linearity was good within the range. At three concentration, the recoveries were 90%~110%; The intra and inter-day RSD was less than 6.5%. The detection limit of erlotinib and OSI-420 were 0.20 ng·m L-1 and 0.25 ng·m L-1,respectively.2.It is found that the pharmacokinetic of single dose group differs from the combination with broneol groups.Compared with the single dose group, the AUC and Cmax of erlotinib are much smaller in combination groups. However, compared with the single dose group, the AUC and Cmax of OSI-420 were significantly larger in the combination groups. Both erlotinib and OSI-420 could penetrate the blood-brain barrier, and their penetration rates in brian tissue were 9.4% and 7.5%, respectively. Through combination with broneol, their penetration rates were significantly higher.3.It is found that the pharmacokinetic of single dose group differs from the combination with quercetin groups. Compared with the single dose group, the tmax of combination groups is much longer(120min vs 60 min). the combination with quercetin groups have larger AUC and Cmax of erlotinib, while smaller AUC and Cmax of OSI-420. The high dose of quercetin group has higher penetration rates of both erlotinib and OSI-420 in brian tissue than single dose group and low dose of quercetin group.Conclusion 1.With the accurate, rapid and stable characters, the UPLC-MS method is suitable for the determination of concentrations of erlotinib and OSI-420 in the mice plasma and brain.2.Borneol could enhance the penetrating blood-brain barrier of erlotinib and OSI-420, but induce the AUC and Cmax of erlotinib in the plasma and brian of mice.Then borneol might not appear to be a assisting agent in the therapeuties of non-small cancer with brain metastasis.3.Quercetin could enhance the penetrating blood-brain barrier of erlotinib and OSI-420, and also increase the AUC and Cmax of erlotinib in the plasma and brian of mice. Quercetin appeared to be a assisting agent in the therapeuties of non-small cancer with brain metastasis.