吉非替尼乳剂单次与多次给药后在大鼠体内的药动学研究

目的:研究吉非替尼乳剂单次和多次给药后在大鼠体内的药动学特征。方法:将大鼠分为单次给药组和多次给药组。单次给药组大鼠分为吉非替尼原料药组(50 mg/kg)和吉非替尼乳剂组(50 mg/kg),每组6只,灌胃给药1次。多次给药组大鼠分为吉非替尼原料药组(50 mg/kg)和吉非替尼乳剂组(50 mg/kg),每组8只,连续灌胃给药7 d,每天1次。吉非替尼原料药组大鼠于给药前和给药后1、2、2.5、3、3.5、3.75、4、4.25、4.5、6、8、12和24 h取血0.3 mL,吉非替尼乳剂组大鼠于给药前和给药后(多次给药组为给药7 d后)2、4、6、8、9、10、11、12、13、14、16、24、36和48 h取血0.3 mL,采用高效液相色谱法测定大鼠血浆中吉非替尼的血药浓度,绘制药-时曲线,并用DAS 2.0软件拟合药动学参数。结果:单次给药后,与吉非替尼原料药组tmax[(2.67±0.75)h]、MRT0-24 h[(8.68±0.91)h]、MRT0-∞[(14.20±3.45)h]比较,吉非替尼乳剂组tmax[(8.33±4.41)h]、MRT0-48 h[(15.00±1.60)h]、MRT0-∞[(17.60±2.66)h]均显著增加(P<0.05)。多次给药后,与吉非替尼原料药组tmax[(6.79±3.75)h]、AUC0-48 h[(41.10±8.92)mg·h/L]、Vz/F[(16.30±5.45)L/kg]、CLz/F[(0.94±0.19)L/(h·kg)]、MRT0-48 h[(10.10±0.36)h]比较,吉非替尼乳剂组Vz/F[(44.20±30.30)L/kg]、CLz/F[(1.89±1.56)L/(h·kg)]、MRT0-48 h[(16.20±2.52)h]均显著增加(P<0.05),AUC0-48 h[(38.70±26.20)mg·h/L]显著减少(P<0.05),tmax[(10.40±3.25)h]增加,但差异无统计学意义。结论:与吉非替尼原料药比较,单次和多次给药吉非替尼乳剂,均可延长药物的达峰时间;本研究结果可为吉非替尼新型给药系统的研究提供参考。

Pharmacokinetic Study on Single and Multiple Administration of Gefitinib Emulsion in Rats

OBJECTIVE:To study pharmacokinetic characteristics of single dose and multiple dose administration of Gefitinib emulsion in rats. METHODS:The rats were divided into single administration group and multiple administration group. Single administration group was subdivided into Gefitinib raw medicine group(50 mg/kg,i.g.)and Gefitinib emulsion group(50 mg/kg,i.g.),with 6 rats in each group,gavage once. Multiple administration group were subdivided into Gefitinib raw medicine group(50 mg/kg)and Gefitinib emulsion group(50 mg/kg),with 8 rats in each group;they were given relevant medicine intragastricaly for consecutive 7 d,once a day. 0.3 m L blood of rats in Gefitinib raw medicine group was taken before medication and 1,2,2.5,3,3.5,3.75,4,4.25,4.5,6,8,12 and 24 h after medication;0.3 m L blood of rats in Gefitinib emulsion group was taken before medication and 2,4,6,8,9,10,11,12,13,14,16,24,36 and 48 h after administration(Multiple administration group is after 7 d of administration). HPLC method was used to determine the plasma concentration of gefitinib in rat,and plasma concentration-time curves were drawn. Pharmacokinetic parameters were fitted by using DAS 2.0 software. RESULTS:After single administration,compared with the tmax[(2.67 ± 0.75)h],MRT0-24 h[(8.68 ± 0.91)h],MRT0-∞[(14.20 ± 3.45)h] of Gefitinib raw medicine group,tmax[(8.33±4.41)h],MRT0-48 h[(15.00±1.60)h],MRT0-∞[(17.60±2.66)h] of Gefitinib emulsion group were increased significantly(P<0.05). After multiple administration,compared with the tmax[(6.79±3.75)h],AUC0-48 h[(41.10±8.92)mg·h/L],Vz/F [(16.30 ± 5.45) L/kg],CLz/F [(0.94 ± 0.19)L/(h·kg)], MRT0-48 h[(10.10 ± 0.36) h] of Gefitinib raw medicine group,Vz/F [(44.20 ± 30.3) L/kg],CLz/F[(1.89 ±1.56) L/(h·kg)],MRT0-48 h[(16.20 ± 2.52) h] of Gefitinib emulsion group were increased significantly(P<0.05),AUC0-48 h[(38.70±26.20)mg·h/L] was decreased significantly(P<0.05),and tmax[(10.40 ± 3.25) h] was increased, without statistical significance. CONCLUSIONS: Compared with Gefitinib raw medicine,single and multiple administration of Gefitinib emulsion can effectively prolong the peak time,the results of this study can provide reference for new delivery system study of Gefitinib.