【摘要】 目的在小鼠体内,探讨吡嗪酰胺每日给药1次与给药3次在药代动力学上的差别,为吡嗪酰胺的合理应用提供依据。方法将平均体质量(18±2)g的6周龄BALB/c小鼠分为5组,每组30只。分别为单独使用吡嗪酰胺1次/d和3次/d给药组(1组和2组)、单独使用异烟肼-利福平组(3组)、异烟肼-利福平联用吡嗪酰胺1次/d和3次/d给药组(4组和5组)。给药后不同时间点取血,液相色谱-质谱联合检测血药浓度,并计算药代动力学参数血药浓度-时间曲线下面积(AUC)、峰浓度(C max)、达峰时间(T max)和半衰期(T1/2)。结果吡嗪酰胺单独给药时,1次/d给药组C max为(155.3±5.1)μg/ml,AUC0~8 h(8 h内药时曲线下面积)为269.5 mg·h/L,分别是3次/d给药组C max(43.2±2.6)μg/ml,AUC0~8 h70.9 mg·h/L的3.5倍以上(t=27.71,P<0.01);当吡嗪酰胺联用异烟肼、利福平给药时,1次/d给药组C max为(151.8±17.3)μg/ml,AUC0~8 h383.1 mg·h/L也远远高于3次/d给药组C max(45.1±1.0)μg/ml,AUC0~8 h81.0 mg·h/L(t=8.718,P<0.05)。而且,当联用异烟肼、利福平并3次/d给药时,吡嗪酰胺对异烟肼有拮抗作用,使异烟肼的C max和AUC0~8 h分别由(6.1±0.9)μg/ml和6.6 mg·h/L下降为(0.05±0.001)μg/ml和0.2 mg·h/L。结论小鼠体内,吡嗪酰胺1次/d给药药代动力学参数优于3次/d给药,尤其是和异烟肼-利福平联用时。更多还原

【Abstract】 Objective To standardize and rationalize the pyrazinamide( PZA) treatments,pharmacokinetic methods were used to evaluate once-daily and thrice-daily regimens in mice. Methods One hundred and fifty BALB/c mice( 18 ±2 g,6 weeks) were divided into 5 groups,30 mice in each group. Group 1 and 2 treated with PZA,once-daily and3 times/day separately,group 3 treated with isoniazid( INH) and rifampicin( RFP),group 4 and 5 treated with INH-RFP and once-daily or 3 times/day PZA. Blood samples were collected from 3 mice of each group at different time point after the seventh dose and pooled separately. Serum INH,RFP and PZA levels were determined by HPLC-MS/MS methods. Pharmacokinetic parameters( AUC,C max,T max and T1/2) were calculated. Results Without INH-RFP,C max and AUC0~8 h of PZA in once-daily regimen were( 155. 3 ± 5. 1) μg/ml and 269. 5 mg·h/L separately,at least 3. 5 folds than in 3 times/day group( C max( 43. 2 ± 2. 6) μg/ml,AUC0~8 h70. 9 mg·h/L,t = 27. 71,P < 0. 01). When combined with INH-RFP,C max( 151. 8 ±17. 3) μg/ml and AUC0~8 h( 383. 1 mg·h/L) of PZA in once-daily group is much higher than thrice-daily regimen group( C max( 45. 1 ±1. 0) μg/ml,AUC0~8 h81. 0 mg·h/L,t = 8. 718,P < 0. 05). Also,PZA antagonized INH in thrice-daily regimen when combined with INH-RFP,accompanied by decreased C max( from( 6. 1 ±0. 9) μg/ml to( 0. 05 ±0. 001) μg/ml) and AUC0~8 h( from 6. 6 mg·h/L to 0. 2 mg·h/L) of INH. Conclusion In mice,pharmacokinetic parameters once-daily regimen for PZA is better than 3 times/day regimen,especially in concomitant treatment with INH-RFP.更多还原