小鼠口服3种苯并咪唑类药物的油酸、大豆油和1%西黄耆胶混悬剂的药动学

Pharmacokinetics of Three Benzimidazoles Suspended in Oleic Acid,Soybean Oil or 1% Tragacanth,and Administered Orally to Mice at A Single Dose

目的观察3种苯并咪唑类药物(阿苯达唑、芬苯达唑或氟苯达唑)的3种混悬剂(油酸、大豆油和1%西黄耆胶的混悬剂)在小鼠体内的药动学参数及其在相应介质中溶解度和生物利用度的相关性。方法用球磨机制备阿苯达唑、芬苯达唑或氟苯达唑在油酸、大豆油和1%西黄耆胶的混悬剂(作对照剂型)。每组45～54只小鼠1次口服1种上述的苯并咪唑类药物混悬液,剂量除阿苯达唑选用100 mg.kg-1外,其余芬苯达唑和氟苯达唑均为50 mg.kg-1,并于给药后0.25～24 h的不同间隔时间取血,用高效液相色谱法测定血药浓度,用DAS程序计算3种苯并咪唑类药物的药动学参数。结果小鼠口服3种苯并咪唑类药物在油酸、大豆油和1%西黄耆胶混悬剂后,阿苯达唑的平均滞留时间(MRT)分别为(3.91±0.29)、(3.70±0.09)和(1.59±0.14)h,峰浓度(ρmax)分别为(0.66±0.08)、(0.29±0.05)和(0.34±0.09)mg.L-1,药物浓度-时间曲线下面积(AUC)分别为(3.19±0.40)、(1.25±0.09)和(0.50±0.05)mg.L.h-1,相对生物利用度F(油酸或大豆油混悬剂组的AUC与1%西黄耆胶混悬剂组AUC之比,下同)分别为6.38和2.50;芬苯达唑的MRT分别为(5.72±0.14)、(4.83±0.38)和(3.85±0.25)h,ρmax分别为(0.70±0.11)、(0.20±0.05)和(0.12±0.03)mg.L-1,AUC分别为(5.02±0.73)、(1.08±0.21)和(0.52±0.07)mg.h.L-1,F分别为9.65和2.08;氟苯达唑的MRT分别为(5.71±0.37)、(4.59±0.39)和(3.34±0.20)h,ρmax分别为(0.93±0.14)、(0.58±0.09)和(0.41±0.09)mg.L-1,AUC分别为(6.90±0.73)、(3.33±0.39)和(1.94±0.55)mg.h.L-1;F分别为3.57和1.72。结论小鼠一次口服阿苯达唑、芬苯达唑或氟苯达唑的2种油相混悬剂后,与1%西黄耆胶混悬剂相比,其药动学参数明显改善,延长了MRT,提高了ρmax,同时增加了AUC和F,而且3种苯并咪唑类药物在3种介质中的溶解度与其在小鼠体内的MRT、ρmax、AUC基本呈正相关。

OBJECTIVE To determine the pharmacokinetics of three benzimidazoles （albendazole, fenbendazole and fluben- dazole） suspended in three different media [ oleic acid, soybean oil or 1% tragacanth （served as control） ] in mice, and observe the correlation of those pharmacokinetic parameters with the solubilities of the three benzimidazoles in corresponding medium. METHODS Albendazole, fenbendazole and flubendazole suspened in oleic acid, soybean oil or 1% tragacantb were prepared by ball grinding mill. Groups of 45 -54 mice were administered orally with one of aforementioned benzimidazole suspensions at a single dose of 100 mg · kg^ - 1 （albendazole） or 50 mg · kg^ - 1 （ fenbendazole and flubendazole）. Subgroups with 5 - 6 mice in each group were bled at var- ying intervals within 24 h. Plasma was then separated from heparin-anticoagulated blood, and evaluated for the presence of the drug by high performance liquid chromatography （HPLC）. Pharmacokinetic parameters of each drug were calculated using DAS （ Drug AnaLyze System）. RESULTS After oral administration of three benzimidazoles suspended in oleic acid, soybean oil or 1% tragacanth, the pharmacokinetic parameters of each drug were described as follows： albendazole, the MRT （average retention time） were （3.91 ± 0. 29）, （3.70 ± 0. 09） and （ 1.59 ±0. 14） h, Pmax （ maximum concentration） were （0. 66 ±0. 08 ）, （0. 29± 0. 05 ） and （ 0. 34±0. 09） mg · L^-1 , AUC （area under the concentration-time curve） were （3.19 ±0. 40）, （1.25±0. 09） and （0. 50 ±0.05） mg · L · h^-1 , F （relative bioavailability, the AUC compared with that of 1% tragacanth group） were 6. 38 and 2. 50; fenbendazole, the MRT were （5.72±0.14）, （4.83 ±0.38） and （3.85 ±0.25） h, pmaxwere（ 0.70±0.11）, （0.20 ±0.05） and （0.12±0.03） mg· L^-1 , AUC were （5.02 ±0. 73）, （1.08±0. 21） and （0. 52±0.07） mg · h· L^-1, F were 9.65 and 2. 08; flubendazole, the MRT were （5.71 ±0.37）, （4.59±0.39） and （3.34±0.20） h, PmaxWere （0.93±0.14）, （0.58±0.09） and （0.41±0.09） mg· L^-1, AUCwere （6.90±0.73）, （3.33 20.39） and （1.94±20.55） mg·L·h^-1, Fwere3.57 and 1.72. CONCLUSION After oral administration to mice, the major pharmacokinetic parameters of the three benzimidazoles suspended in oleic acid and soybean oil show significant improvement compared to those of the same drugs suspended in 1% tragacanth, which manifest as prolongation of MRT, and increase of p AUC as well as F. The solubilities of the three benzimidazoles in three different media were on the whole positive correlative to their MRT, p AUC and F in mice.