Effects Of Borneol On The Pharmacokinetics Of Vinpocetine In Rats

Objective:Vinpocetine（VP）,a semi-synthetic derivant of vincamine,which is fat-soluble and gererally recognized as a brain activator,can effectively improve the cerebral circulation and metabolism.It has been widely used to alleviate cerebral ischemia-related diseases in clinical practice.Borneol is a small fat-soluble molecular that can increase the biofilm barrier permeability,open cell attachment,and was used to promote the absorption and tissue distribution of central nervous system drugs in often.VP is poorly soluble in water,which has a short elimination half-life and represents a significant first-pass effect.In this study,borneol of different dosage were applied with VP in rats,as borneol is able to open blood–brain barrier（BBB）.The effects of borneol on the pharmacokinetics of VP in rats were investigated in this article by the comparisons among the borneol and VP combined administration groups and the VP single administration group.Methods:The rats were divided in random into three groups:VP single administration group（10 mg/kg）,VP combined with high dose of borneol（borneol 150 mg/kg）and VP combined with low dose of borneol group（borneol 75 mg/kg）,after i.g.of the drugs above,the blood samples at different time points were collected for detection.The concentration of VP in plasma was quantified by LC-MS/MS method to plot the time-concentration curve and the main pharmacokinetic parameters were calculated using the non-compartmental model.Some other two groups of rats were administrated with VP alone（10 mg/kg）and VP combined with high dose of borneol（borneol 150 mg/kg）,respectively.After i.g.,the rat’s brain and liver tissue samples were collected and homogenized,and the concentration of VP in brain and liver tissue was quantified to calculate the tissue exposure of VP.Liquid chromatography conditions:column:Shimadzu Shim-pack XR-ODSⅢC₁₈chromatographic column（75 mm×2.0 mm,1.6μm）;mobile phase:A:0.1%formic acid-water,B:acetonitrile,（A:B=70:30,v/v）,isocratic elution;flow rate:0.4 ml/min;column temperature:40°C;injection volume:10μL,analysis time:3.0 min.Mass spectrometry conditions:ESI ion source,ion spray voltage of-4.5 KV,positive ion multiple reaction monitoring mode（MRM）was used for quantitative analysis of the ion pairs:VP m/z 350.10→m/z 280.10,CE（collision energy）:-33 V;internal standard phenacetin m/z 180.00→m/z110.15,CE:-21 V;heating block temperature:400°C,atomization gas（N₂）flow rate:3.0L/min;dry gas（N₂）flow rate:15.0 L/min.Results:The LC-MS/MS method that used for quantification of VP in biological samples has a good linearity and the endogenous substances in the biological samples did not interfere with the quantification of VP.The AUC_0-∞values of the three groups（VP administration group,VP combined with high dose of borneol and VP combined with low dose of borneol group）were 1220.2±328.0μg·h/L、1561.2±439.5μg·h/L and 2413.8±448.9μg·h/L,respectively;the C_max values were 422.0±192.0μg/L、382.9±74.3μg/L and470.3±66.7μg/L;the t_1/2z values were 2.6±1.8 h、4.3±2.0 h and 3.7±1.3 h.Among them,the difference between AUC_0-∞of VP alone group and high dose borneol combined group was extremely significant（p﹤0.01）and the difference of t_1/2z（p﹤0.05）between the two groups mentioned was statistically significant.The AUC_0-4t1/2 of brain,liver and kidney tissue after i.g.of VP alone and VP combined with high dose of borneol was calculated.In brain,the AUC_0-4t1/2 value of high dose borneol combined group is 3651.4 ng/g?h,the AUC_0-4t1/2 value of VP alone group is 2833.8 ng/g?h;in liver,the AUC_0-4t1/2 value of high dose borneol combined group is 17816.2 ng/g?h,the AUC_0-4t1/2 value of VP alone group is 11853.5 ng/g?h in kidney,the AUC_0-4t1/2 value of high dose borneol combined group is 9225.1ng/g?h,the AUC_0-4t1/2 value of VP alone group is 6170.4 ng/g?h.Conclusion:The combination of borneol with VP,especially high-dose borneol,resulted in a significant increasement of the VP concentration in plasma,and prolonged the residence time in the rats,accelerated the clearance in plasma,increased the amount of VP in brain and liver,indicating the promotion effects on the absorption and distribution of VP in rat’s organization.