| Objective: China is multinational country and every nationality might have difference in the performance of Pharmacokinetic (PK) due to significant disparities of living environment, genetics, eating habit, and so forth. Moreover, many results of the related researches concerning the different gender demonstrated that there exited wide variances between male and female concerning PK performance. Therefore, to instruct the patients of various nationalities of China at the same method might cause possible therapeutic failure and unnecessary adverse effect of fluconazole that is a widely used antifungal agent of the azoles in clinic with characters of a prolonged half time and drug interaction with coadministration of various drugs.The aim of the study is to investigate and compare the PK of fluconazole tablet in healthy volunteers of different Chinese nationalities (including Han, Mongolia, Korean, Muslim and Uigur) and genders. In addition, to provide instruction and help for the usage of fluconazole safely, reasonable and effectively to both clinic and remedy of battle wound.Methods: A single oral dose of 200mg fluconazole was given under fasting conditions to fifty healthy volunteers of related Chinese nations above (twenty-five are male and the rest are female). Blood samples were obtained before dosing and at various predetermined time points after administration up to 96 hours. A simple, accurate, precise and sensitive high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed and validated for quantification of fluconazole in plasma samples after liquid–liquid extraction. The software program DAS(Drug And Statistics,version 2.0) was developed as a tool to calculate PK parameters representing absorption (AUC, Cmax, tmax), distribution (Vd), metabolism (t1/2) and excretion (CL) of different nationalities and genders. Analysis of variance (ANOVA) and Kruskal-Wallis rank test for different PK parameters were used for the assessment of effects concerning nationality and gender. In addition, the correlation analysis between the weight of subjects and their PK parameters were performed for investigating the influence of weight on the PK performance.Results: Linearity of fluconazole in the plasma was between 0.15 and 10.00mg·L-1. The lower limit of quantification (LLOQ) of fluconazole was 0.15 mg·L-1. The method recovery is between 93.31% and 105.00% and the recovery of fluconazole plasma samples by liquid-liquid extraction ranged from 82.86 to 84.47%. The within-day precision is lower than 7.40%; moreover, the between-day precision was lower than 12.05%. The method developed for the determination of the fluconazole maintained the requirements of assay for the biological specimen.The PK parameters of fifty healthy volunteers of different nationalities (including Han, Mongolia, Korean, Muslim and Uigur) after administration of 200 mg Fluconazole are as followed : Cmax are (4.91±0.67), (4.90±0.93), (4.70±0.86), (4.99±1.05) and (5.22±1.04) mg·L-1; tmax are (1.90±0.91), (1.55±0.44), (2.55±1.07), (2.30±0.95) and (2.20±1.30)h; t1/2 are (31.43±3.63), (27.98±5.15), (29.52±4.83), (30.47±6.27) and (32.18±6.12)h; Vd are (44.55±9.82), (44.12±13.90), (43.15±6.49), (42.50±9.23) and (43.77±7.70) L; CL are (0.94±0.18), (1.09±0.25), (0.99±0.19), (1.02±0.19) and (0.93±0.26) L·h-1; AUC(0-96h) are (189.62±32.91), (173.95±40.41), (183.75±31.83), (178.59±27.71) and (197.21±49.3) mg·h·L-1; AUC(0-∞) are (219.21±40.45), (192.61±45.30), (209.93±46.37), (202.20±35.26) and (231.97±70.11) mg·h·L-1.The PK parameters concerning fifty healthy volunteers of between male and female after administration of 200 mg Fluconazole are as followed: Cmax are (4.29±0.45) and (5.60±0.72) mg·L-1; tmax are (2.06±1.12) and (2.14±0.83) h; t1/2 are (30.32±5.88) and (30.32±4.72) h; Vd are (50.22±7.29) and (37.01±5.67) L; CL are (1.07±0.21) and (0.92±0.19) L·h-1; AUC(0-96h) are (166.50±26.73) and (202.74±35.47) mg·h·L-1; AUC(0-∞) are (194.96±39.42) and (227.40±51.07) mg·h·L-1.Results of the ANOVA revealed that the difference of the nationality posed little influence on both PK parameters that are transferred by natural logarithm such as Cmax and AUC and ones that are not transferred such as Vd and CL. However, there is statistically significant difference between male and female concerning PK parameters above.Results of Kruskal-Wallis rank test demonstrated that there was not statistically significant concerning tmax, and t1/2 in the healthy volunteers who owned different nationalities and genders.There is high linear correlation between weight and lnCmax, lnAUC (ln means natural logarithmic transformation), Vd, CL and related P-value of the correlation coefficient is lower than 0.001.The main innovation of the paper is as followed: First, It initiated investigation concerning the PK performance of fluconazole in the healthy volunteers from Chinese Mongolia, Chinese Korean, Chinese Muslim and Chinese Uigur. In addition, comparisons concerning PK performance were made between the Chinese Han and the Chinese related nationalities above.Conclusion: The study failed to demonstrate the statistically significant difference of nation between Chinese Han, Mongolia, Korean, Muslim and Uigur had influence on the PK of fluconazole tablet. Moreover, the statistically significant differences of AUC, Cmax,, Vd and CL in the groups of different gender mainly derived from the variance of weight between male and female. |
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