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 and 3 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 T_1/2) were calculated.  Results  Without INH-RFP, C_max and AUC_{0~8 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, AUC_{0~8 h} 70.9 mg·h/L, t=27.71，P<0.01). When combined with INH-RFP, C_max (151.8±17.3)μg/ml and AUC_{0~8 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, AUC_{0~8 h} 81.0 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 AUC_{0~8 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.

Key words: Tuberculosis/drug therapy, Pyrazinamide, Isoniazid, Rifamycin, Pharmacokinetics