盐酸比格列酮缓释微丸在犬体内的药动学与体内外相关性研究

Study of in vivo Pharmacokinetics and Correlation between in vivo and in vitro of Pioglitazone Hydrochloride Sustained-release Pellets in Dogs

目的：研究盐酸比格列酮（PGH）缓释微丸在犬体内的药动学和体内外相关性。方法：将6只Beagle犬随机均分为两组,分别ig给予受试制剂PGH缓释微丸和参比制剂PGH片,给药剂量为0.4 mg/kg,1周后交叉实验。分别于给药前和给药后0.5、1、1.5、2、3、4、5、6、8、10、13、24、36 h取血2 ml制备血浆。采用高效液相色谱法测定其血药浓度,3p97软件计算药动学参数,并考察其体内外相关性。色谱柱为Thermo Hypersil GOLD C18,流动相为甲醇-25 mmol/L乙酸铵水溶液-甲酸（70∶30∶0.2）,流速为1.0 ml/min,柱温为30℃,检测波长为240 nm,进样量为20μl。结果：PGH检测质量浓度的线性范围为0.1-3.2μg/ml（r=0.999 7）,方法回收率为95.0%-101.7%（RSD为4.56%-6.77%,n=3）,提取回收率为67.9%-70.3%（RSD为5.53%-8.72%,n=3）。受试制剂的药-时曲线符合单室模型;受试制剂与参比制剂的tmax分别为（10.59±0.37）、（2.21±0.14）h,t1/2分别为（11.75±0.55）、（6.98±0.39）h,cmax分别为（2.01±0.21）、（2.35±0.33）μg/ml,AUC0-36 h分别为（38.57±5.53）、（33.73±4.31）μg·h/ml;受试制剂相对生物利用度为114.3%;体外释药与体内吸收数据的相关系数r=0.910 3。受试制剂tmax及t1/2较参比制剂明显延长,cmax较参比制剂有所降低。结论：PGH缓释微丸具有缓释特征,体外释药与体内吸收具有相关性。

OBJECTIVE：To study the pharmacokinetics in vivo and correlation between in vivo and in vitro of Pioglitazone hydrochloride（PGH） sustained-release pellets in dogs. METHODS：6 Beagle dogs were randomly divided into 2 groups,and they were ig given tested preparations（PGH sustained-release pellets）and reference preparations（PGH tablets）with 0.4 mg/kg,respectively. A crossover trial was conducted after 1 week. 2 ml blood sample was respectively taken before administration and after 0.5,1,1.5,2,3,4,5,6,8,10,13,24,36 h of administration,and the plasma was collected. The plasma concentration of PGH was determined by HPLC,the pharmacokinetic parameters were calculated by using 3p97 software and the correlation between in vivo and in vitro was observed. The determination was performed on Thermo Hypersil GOLD C18 with mobile phase of methanol-25mmol/L ammonium acetate solution-formic acid（70∶30∶0.2） at the flow rate of 1.0 ml/min,with the column temperature of30 ℃,measurement wavelength of 240 nm and injection volume of 20 μl. RESULTS：The linear range of PGH quality concentration was 0.1-3.2 μg/ml（r=0.999 7）,the method recovery was 95.0%-101.7%（RSD=4.56%-6.77%,n=3）and the extraction recovery was 67.9%-70.3%（RSD=5.53%-8.72%,n=3）. The drug-time curve of the tested preparations was compatible with single-compartment model. The tmaxof the tested preparations and reference preparations were（10.59±0.37）h and（2.21±0.14）h,respectively;t1/2were（11.75±0.55）h and（6.98±0.39）h,respectively;cmaxwere（2.01±0.21）μg/ml and（2.35±0.33）μg/ml,respectively;and AUC0-36 hwere（38.57±5.53）μg·h/ml and（33.73±4.31）μg·h/ml,respectively. The relative bioavailability of the tested preparations was 114.3%. The coefficient r of the correlation between drug release data in vitro and absorption data in vivo was 0.910 3. Compared with the reference preparations,tmaxand t1/2values of the tested preparations were obviously extended and cmaxvalue was decreased. CONCLUSIONS：PGH sustained-release pellets show sustained-release property. The drug release in vitro and absorption in vivo are correlated with each other.