不同剂型普罗布考对大鼠肠系膜淋巴转运及药代动力学的影响

Effects of Probucol Formulations on Mesenteric Lymphatic Transport Efficiency and Pharmacokinetics in Rats

目的通过一种新型的肠系膜淋巴管-颈静脉辅助回流模型,比较普罗布考橄榄油制剂与普罗布考混悬液制剂对大鼠肠系膜淋巴转运及药代动力学的影响。方法12只SD大鼠随机分为4组,即混悬液制剂-颈静脉单插管组(H-JD组)、混悬液制剂-颈静脉和肠淋巴管双插管组(H-JCS组)、橄榄油制剂-颈静脉单插管组(G-JD组)、橄榄油制剂-颈静脉和肠淋巴管双插管组(G-JCS组)。用液相色谱和串联质谱联用(LC-MS/MS)法测定各组大鼠在不同时间全血和淋巴液中普罗布考的浓度,绘制药-时曲线,计算药代动力学参数、相对生物利用度(F_(re))和淋巴液剂量百分比。结果各组的药-时曲线符合非房室模型。前述各组到达峰值时间(T_(max))分别为(11±12)h、(5±2)h、(13±9)h和(19±9)h;到达峰值浓度(C_(max))分别为(148±60)ng/mL、(207±137)ng/mL、(453±204)ng/mL和(309±177)ng/mL;药-时曲线下面积(AUClast)分别为(3210±885)h·ng·mL^(-1)、(3677±2014)h·ng·mL^(-1)、(12360±6629)h·ng·mL^(-1)和(8080±3064)h·ng·mL^(-1)。H-JCS组和G-JCS组的淋巴液剂量百分比分别为(1.29±0.50)%和(2.59±0.43)%。与H-JD组相比,G-JD组中普罗布考的F_(rel)为(409±269)%;与H-JCS组相比,G-JCS组中普罗布考的F_(rel)为(309±256)%。与H-JD组和H-JCS组相比,G-JD组和G-JCS组大鼠全血的C_(max)、T_(max)、AUClast和淋巴液剂量百分比显著升高(P<0.05);其中G-JD组全血的AUClast显著高于G-JCS组(P<0.05),而HJD组和H-JCS组差异无统计学意义(P>0.05)。结论使用橄榄油制剂可以提高普罗布考通过肠系膜淋巴液的转运吸收率和生物利用度。

Objective To compare the effects of probucol olive oil and suspension formulations on the pharmacokinetics and mesenteric lymphatic transport in rats using an innovative mesenteric-jugular lymphatic duct assisted reflux model.Methods Twelve Sprague-Dawley(SD)rats were randomly divided into four groups:suspension preparation-jugular vein single cannulation group(H-JD group),suspension preparation-jugular vein and intestinal lymphatic double cannulation group(H-JCS group),olive oi preparation-jugular vein single cannulation group(G-JD group),olive oil preparation-jugular vein and intestinal lymphatic double cannulation group(G-JCS group).The concentrations of probucol in whole blood and lymph fluid of rats at different times were determined by liquid chromatography and tandem mass spectrometry(LC-MS/MS),and drug-time curves were drawn.The pharmacokinetic parameters,relativebioavailability(F_(rel))and percentage dose in lymph fluid were calculated.Results The drug-time curve of each group conformed to the non-compartmental model.The peak times(T_(max))of the H-JD group,H-JCS group,G-JD group,and G-JCS group were(11±12),(5±2),(13±9),and(19±9)h,respectively;the peak concentrations(C_(max))were(148±60),(207±137),(453±204),and(309±177)ng/mL,respectively;the areas under the curve(AUClast)were(3210±885),(3677±2014),(12360±6629),and(8080±3064)h·ng·mL^(-1),respectively.The percentages of lymphatic fluid dose in the H-JCS and G-JCS groups were(1.29±0.50)%and(2.59±0.43)%.Compared with the H-JD group,the F_(rel)of probucol in the G-JD group was(409±269)%;compared with the H-JCS group,the F_(rel)of probucol in the G-JCS group was(309±256)%.Compared with the H-JD and H-JCS groups,the whole blood values of C_(max),T_(max),AUClast and percentage of lymphatic fluid probucol concentrations of the G-JD and the G-JCS groups were significantly increased(P<0.05).The AUClast of whole blood in the G-JD group was significantly higher than that in the G-JCS group(P<0.05),but there was no significant difference between the H-JD and H-JCS groups(P>0.05).Conclusion Olive oil formulation can improve the ratio of probucol transport through mesenteric lymph as well as its bioavailability.