Paradoxical Effect of Isoniazid on the Activity of Rifampin-Pyrazinamide Combination in a Mouse Model of Tuberculosis
Paradoxical Effect of Isoniazid on the Activity of Rifampin-Pyrazinamide Combination in a Mouse Model of Tuberculosis
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DOI：
10.1128/aac.00830-09
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发表时间：
2009-10-01
影响因子：
4.9
通讯作者：
Grosset, Jacques
中科院分区：
文献类型：
--
作者：
Almeida, Deepak;Nuermberger, Eric;Grosset, Jacques
为了研究在结核分枝杆菌感染的小鼠中观察到的异烟肼（INH）和利福平（利福平）（RIF）-吡嗪酰胺（PZA）组合之间的拮抗作用，进行了广泛的INH药代动力学研究，然后进行实验以评估增加剂量的INH对RIF-PZA组合的抗微生物活性的影响。6.25 mg/kg体重的INH产生的最大血清药物浓度（C-max）值为4 μ g/ml，0 - 24 h浓度-时间曲线下面积（AUC（0-24））值为4.9 μ g。h/ml，前者接近于人体标准剂量5 mg/kg后观察到的C-max值。25 mg/kg INH产生的C-max值为22 μ g/ml，AUC（0-24）值为29 μ g。h/ml，后者接近在具有慢乙酰化表型的人中给予5-mg/kg剂量的INH后观察到的AUC。在用M.在结核病中，用INH以两倍增加的剂量（范围为1.56至50 mg/kg）单独或与RIF-PZA组合治疗小鼠8周。单独给药，INH表现出剂量依赖性活性。INH与RIF-PZA合用后，对RIF-PZA活性的拮抗作用呈剂量依赖性。为了确定RIF-PZA组合中INH具有拮抗性的各个组分，用单独的RIF、单独的PZA、RIF-PZA和单独或与RIF或PZA组合的3.125、12.5或50 mg/kg的INH处理小鼠8周。将INH加入RIF中具有相加活性，而将INH加入PZA中导致负相互作用。最后，小鼠中10 mg/kg剂量的INH可能最能代表人类中5 mg/kg剂量，并降低INH与RIF-PZA的拮抗作用。
To investigate the antagonism between isoniazid (INH) and rifampin ( rifampicin) (RIF)-pyrazinamide (PZA) combination observed in Mycobacterium tuberculosis-infected mice, extensive pharmacokinetic studies of INH were performed and followed by experiments to assess the impact of increasing doses of INH on the antimicrobial activity of RIF-PZA combination. INH at 6.25 mg/kg of body weight produced a maximum concentration of drug in serum (C-max) value of 4 mu g/ml and an area under the concentration-time curve from 0 to 24 h (AUC(0-24)) value of 4.9 mu g . h/ml, the former being close to the C-max value observed after the standard 5-mg/kg dose in humans. INH at 25 mg/kg produced a C-max value of 22 mu g/ml and an AUC(0-24) value of 29 mu g . h/ml, the latter being close to the AUC observed after a 5-mg/kg dose of INH in humans with the slow acetylation phenotype. Beginning 2 weeks after aerosol infection with M. tuberculosis, mice were treated for 8 weeks with INH at twofold-increasing doses, ranging from 1.56 to 50 mg/kg, either alone or in combination with RIF-PZA. Given alone, INH exhibited dose-dependent activity. Combined with RIF-PZA, INH exhibited dose-dependent antagonism of RIF-PZA activity. To determine the individual components of RIF-PZA combination with which INH was antagonistic, mice were treated for 8 weeks with RIF alone, PZA alone, RIF-PZA, and INH at 3.125, 12.5, or 50 mg/kg either alone or combined with RIF or PZA. Addition of INH to RIF had additive activity, whereas addition of INH to PZA resulted in a negative interaction. Finally, a 10-mg/kg dose of INH in mice may best represent the 5-mg/kg dose in humans and decrease the antagonism of INH with RIF-PZA.