| ObjectiveThe pharmacokinetics of Azithromycin Dispersible Tablets ( AZM ) between tested ( developed by Zhongfa Industry Combine Yerui Medicine Ltd, 250mg/ tab) and referenced (produced by Hainan Currency Confederation Medicine Ltd, 250mg/tab) , were determined after randomized crossover administration 500mg orally in 18 healthy Chinese volunteers. The drug concentrations of different time in plasma were measured by microbiological assay. The main pharmacokinetics parameters and relative bioavailability were calculated by 3p97 software to help clinical therapy.Method1. Administration of drugThis trial was an open - label, randomized crossover study. Subjects who met study eligibility criteria were randomly assigned to two groups ( tested and referenced ). Each group were administered a single oral dose of 500 mg AZM, respectively , with 3 weeks washout interval . Both drugs were taken with 250ml boiled water.2. Collection of blood samplesVenous blood samples (4ml) for determining plasma level of AZM were collected immediately before and after oral administration at 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 48.0, 96.0, 120.0, 144.0 h, respectively. Plasma was separated by centrifugation for 10 min (3000r ? min"1). The specimens were stored at refrigerator( -40^C ) until to be analyzed.3. Microbiological assayAgar plate diffusion method;After high - pressure steam sterilization, nutritive medium was put in constant temperature of 50T1 for lh;Sarcina lutea was used as test organism and put into the nutritive medium(50X.). After coagulation, perforated with pinhole plotter ( diametter = 5 cm).Application of sample;Standard dilutions of the antibiotic were prepared in pooled human serum phosphate buffer at pH7. 8 ~ 8.0. and added into the holes(35 jxl) according to the dilution, while blood samples with unknown concentration were added in the same plate. Every sample repeat twice. After cultivating at 35T! for 18h, measure the diameter of bacteriostasis collars. And then calculate the standard curve.Results1. Identification of determination of AZM in plasma1. 1 Microbial assay of AZM and the specifityOperated as Microbiological Assay, bacteriostasis collar can be observed in plasm with AZM,while no bacteriostasis collar be observed in blank plasm. That indicate the certainty and reliability of the method.1. 2 Standard curveAZM of various known concentration was added to plasma at the final concentration of 0.01, 0.025, 0.05 x0.10, 0. 20, 0.40, 0. 60, 0. 80, 1.60jxg ? mL"1. They were processed according to the above procedure. The linear regression was constructed by the diameter of the AZM ( O) an logarithm concentration ( [xg ? mL"1) of the drug in plasma (logC). Satisfatory linearity was observed in the range of 0. 01 -1.6 \xg ' mL~ of the drug. The regression equation was logC =2.3535 + 0. 89980 (r = 0. 9985 ,n = 9). The detectable limit of AZM under these conditions was O.Oljxg ? mL" .1. 3 Relative recovery and intra — day, inter - day precisionPlasma samples (n = 5 ) with the final concentrations ofO.Ol, 0.1, 0.8 |xg ? ml ~ of AZM were extracted according to the procedure mentioned above. These samples were treated according to the above inter - day and within - day repeatedly. The recovery of the compound was calculated by comparing the experimental value with the corresponding theoretical value. The mean relative recovery of AZM was above 90% ,The coefficients of variation of within - day and inter - day were both less than 15%.2. Study of Pharmacokinetics 2. 1 Concentrations of AZMThe plasma samples were performed by " Microbial Assay" , and then cultivate and record the diameter. Concentrations of AZM were calculated by standard curvilinear equation.2. 2 Pharmacokinetic parametersThe data of AZM& concentrations were disposed and analysed by 3p97 software and calculate the pharmacokinetic parameters, we adopted trapezoidal rule to calculate AUC0_tand AUCq.^. k and t1/2%TmMXCmaxwere calculated through concentrations of elimination phase and semilogarithm - figure. The results indicate that Tmax(h)of AZM was 1.65 ±0.64, 1.60 ±0.65,and Cmax( p.g/ml)was 0.45 ±0. Hand 0.52 ± 0. 27;t1/2 (h) was 0. 80 ± 0. 33.0. 79 ± 0. 35;from the trapezoidal rule, AUC0_t (jxg ? h/ml) was 6. 69 ± 1. 86, 6. 88 ± 1.24jxg ? h/ml;AUCO_X (|xg ? h/ml) was 8. 95 ± 1. 87, 9.31 ±1. 55. According to the data of AUC0_t,the average relative bioavailability of AZM adds up to 98. 92 ±26. 62%.ConclusionsWe deal with the date by analysis of variance and two - one sided test, to judge the bioequiavilability of tested and reference drugs. AUC0_t of tested belongs to 87.4% ~ 104.0% corresponding parametric 90% confidence interval of referencejAUCo.^of tested belongs to 88. 5% ~ 102. 9%;Craax90% confidence interval of tested is 75.0% ~ 105. 3% and90% confidence interval of C/AUCis 100.3%-114.2%.
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