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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 observe the effects of three suspensions of oleanolic acid, soybean oil and 1% tragacanth on three benzimidazoles (albendazole, fenbendazole or flubendazole) Pharmacokinetic parameters in mice and their correlation with solubility and bioavailability in corresponding media. Methods A suspension of albendazole, fenbendazole or flubendazole in oleic acid, soybean oil and 1% tragacanth was prepared by ball mill. One group of 45 ~ 54 mice in each group were orally administered with one of the above benzimidazole suspensions. The doses of fenbendazole and flubendazole in addition to albendazole were 100 mg.kg-1 50 mg.kg-1. Blood samples were collected at different intervals of 0.25-24 h after administration. Plasma concentrations were determined by HPLC. The pharmacokinetics of three benzimidazoles were calculated by DAS program parameter. Results The average retention time (MRT) of albendazole in mice after oral administration of 3 benzimidazoles in oleic acid, soybean oil and 1% tragacanth was respectively 3.91 ± 0.29 and 3.70 (0.66 ± 0.08), (0.29 ± 0.05) and (0.34 ± 0.09) mg.L-1, respectively. The area under the drug concentration-time curve (AUC ) Were (3.19 ± 0.40), (1.25 ± 0.09) and (0.50 ± 0.05) mg.Lh-1 respectively.The relative bioavailability F (AUC of oleic acid or soybean oil suspension group and 1% (5.72 ± 0.14), (4.83 ± 0.38) and (3.85 ± 0.25) h, respectively, and ρmax were (0.70 ± 0.12, 0.11, 0.12 ± 0.03 and 0.12 ± 0.03 mg.L-1.AUC was (5.02 ± 0.73), (1.08 ± 0.21) and (0.52 ± 0.07) mg.hL-1, respectively And 2.08, respectively. The MRT of flubendazole were (5.71 ± 0.37), (4.59 ± 0.39) and (3.34 ± 0.20) h, respectively, and the ρmax were 0.93 ± 0.14, 0.58 ± 0.09 and 0.41 ± 0.09, mg.L-1 and AUC of (6.90 ± 0.73), (3.33 ± 0.39) and (1.94 ± 0.55) mg.hL-1, respectively; F was 3.57 and 1.72, respectively. Conclusions After oral administration of two kinds of oily suspensions of albendazole, fenbendazole or flubendazole, the pharmacokinetic parameters of the two oily suspensions were significantly improved compared with 1% Prolongation of MRT, increase of ρmax, increase of AUC and F, and the solubility of three benzimidazoles in three media has a positive correlation with their MRT, ρmax and AUC in mice.