阿苯达唑新剂型的药代动力学研究

INITIAL OBSERVATION OF PHARMACOKINETICS IN DIFFERENT CARRIER FOR ALBENDAZOLE

目的 通过药代动力学研究 ,为选择高效杀棘球蚴药物阿苯达唑 (Albendazole ,ABZ)新剂型提供参考。 方法 选用 2 4只健康Wistar大鼠 ,随机分为 4组 :大分子物 (Macrosol) ABZ(Mac ABZ)组、脂质体 (Liposome) ABZ(L ABZ)组、前体脂质体 (Pre liposome) ABZ(Pre L ABZ)组及片剂ABZ组。按ABZ 5 0mg/kg经口灌药 ,分别于灌药后 1、2、3、4、5、6、7、8、12、2 4、3 6、48h采尾静脉血 ,用HPLC法测定血中ABZ及其代谢产物砜 (ABZSN )和亚砜 (ABZSX )浓度。血药浓度数据用 3P87药代动力学程序软件包分别进行模型嵌合。以Akaie’s信息判断AIC值、回归系数、拟合优度等。用PEMSVer 2 .1统计软件进行显著性检验 ,确定药物在体内的配置状态 ,观察其药代动力学特征。 结果 1)Pre L ABZ :相对于片剂ABZ ,Pre L ABZ剂型中ABZ的相对生物利用度为 14 6.5 4% (P >0 .0 5 ) ,ABZSX为 2 67.76% (P <0 .0 1) ,ABZSN为 15 5 .2 9% (P <0 .0 1) ;Pre L ABZ的消除速度常数 (β)为 (0 .0 5± 0 .0 2 )l/h ,半衰期 (t1/ 2 β)为 (17.16± 6.48)h ,清除率 (CL)为 (0 .0 6± 0 .0 1)ng/ml。片剂ABZ的 β为 (0 .10± 0 .0 4)l/h ,t1/ 2 β为 (6.60± 2 .0 3 )h ,CL为 (0 .11±0 .0 4)ng/ml ,差异均有显著性 (P <0 .0 5 )。

Objective To study the pharmacokinetics of albendazole(ABZ) combined with different biologic carriers, so as to improve the effect of ABZ against echinococcosis. Methods 24 healthy Wistar rats were randomly divided into 4 groups. Each group was orally administered by the same ABZ dosage at 50 mg/kg. ABZ concentration and its metabolites [(ABZ sulfoxide, ABZSX), (ABZ sulphone, ABZSN)] were measured by HPLC at different sampling time. Results ①Pre-liposome-ABZ(Pre-L-ABZ) formulation: 1) Relative bioavailability: Pre-L-ABZ formulation versus ABZ tablet, the ABZ was 146.54%(P>0.05), ABZSX was 267.76%(P<0.01), ABZSN was 155.29%(P<0.01); 2) Pharmacokinetics: In ABZ tablet, β was (0.10±0.04) l/h, t1/2β was (6.60±2.03) h, CL was (0.11±0.04) ng/ml. In the Pre-L-ABZ, β was (0.05±0.02) l/h, t1/2β was (17.16±6.48) h, CL was (0.06±0.01) ng/ml. Compared with ABZ tablet, P<0.05;3) Organ target: The K 12 for Pre-L-ABZ was (0.15±0.07) l/h. Compare with ABZ tablet [(0.03±0.02) l/h], P<0.01;4) Drug concentration in plasma: The concentration of Pre-L-ABZ at every time point was significantly difference compared with ABZ tablet( P<0.01)?②Macrosol-ABZ(Mac-ABZ): 1) Absorption rate (Ka): ABZ tablet was (0.38±0.18) l/h, Mac-ABZ was (0.81±0.24) l/h (P<0.05);2) Relative bioavailability: Mac-ABZ formulation versus ABZ tablet, ABZ was 76.53%(P>0.05), ABZSX was 192.27%(P<0.01), ABZSN was 283.45%(P<0.01);3) Drug concentration in plasma: Mac-ABZ concentration at each time point was significantly difference compared with ABZ tabletP<0.01). Conclusion Macrosol, liposome, pre-liposome as a drug carrier, can increase the concentration of ABZ and its metabolites, prolong the metabolism, and increase the relative bioavailability for ABZSX and ABZSN. Both pre-liposome and macrosol formulation showed interesting advantages as drug deliver systems which could be benefit to anti-hydatid chemotherapy. Further experimental investigation need to be done for the conformation of its anti-hydatid effect and potential clinical application.