非诺贝特纳米混悬剂大鼠体内药动学及其与在体肠吸收动力学相关性

Pharmacokinetics of fenofibrate nanosuspension in vivo and its correlation to intestinal absorption kinetics in situ in rats

目的考察非诺贝特纳米混悬剂体内药动学及其与在体肠吸收动力学的相关性。方法 12只SD大鼠,随机分为两组,分别给予非诺贝特原料药或非诺贝特纳米混悬剂灌胃,剂量均为27 mg·kg^(-1)。建立高效液相色谱法(HPLC)检测大鼠血药浓度,并进行药动学参数拟合及组间比较。另取大鼠6只进行在体肠灌注观察肠吸收情况,采用HPLC法检测肠循环液中非诺贝特及非诺贝特酸含量。计算药物体内吸收百分率(F)及在体吸收百分率(P),进行相关性评价。结果体内药动学特征符合一室模型,原料药组和纳米混悬剂组AUC_(0-36)分别为(34.39±12.71)和(492.64±112.19)μg·h·mL^(-1),c_(max)分别为(3.56±1.24)和(39.19±2.55)μg·mL^(-1),组间差异非常显著(P<0.01);两组t_(max)分别为(2.47±0.16)和(1.95±0.72)h,纳米混悬剂低于原料药组,但组间无显著差异(P>0.05)。F与P有较好的相关性,线性方程:F=3.691 1P-2.216 9,r=0.970。结论非诺贝特纳米混悬剂生物利用度高,在体内吸收迅速且充分,其肠吸收动力学结果可用于预测人体对药物的吸收情况。

AIM To study the pharmacokinetics of fenofibrate nanosuspension in vivo and its correlation to intestinal absorption kinetics in situ in rats. METHODS Twelve SD rats were randomly divided into two groups, and freshly prepared fenofibrate nanosuspension or coarse suspension was administrated of 27 mg·kg-1 to rats by gavage. The plasma concentration was determined by HPLC method and pharmacokinetic parameterswere calculated by 3P97 software. Another six rats were used in the intestinal absorption in situ experiment by circulation method, while HPLC was used to determine the concentrations of fenofibrate and fenofibric acid. The correlation between absorption in vivo （F） and intestinal absorption in situ （P） in rats was investigated. RESULTS The plasma concentration- time curve was fitted to a one- compartment model. The main pharmaeokinetie parameters of coarse suspension and fenofibrate nanosuspension were as follow： AUC0.36 （34.39 ± 12.71） and （492.64 ± 112.19） μg·h-mL-1 （P〈 0.01）, c/max （3.56 ± 1.24） and （39.19 ± 2.55） μg·mL-1 （P〈 0.01）, t/max （2.47 ± 0.16） and （1.95 ± 0.72） h （P 〉 0.05）. Correlation between intestinal absorption in situ and gastric perfusion of fenofibrate nanosuspension in rats was satisfactory. The linear equations for F and P at corresponding time points were as follow： F = 3.691 1P - 2.216 9, r = 0.970. CONCLUSION Fenofibrate nanosuspension has higher bioavailability, quicker and adequate absorption. The results of intestinal absorption kinetics experiment could be helpful in the prediction of the drug absorption in human.