计算机模拟的地塞米松鼓室给药途径在人内耳外淋巴液的药物动力学研究

Quantitative interpretation of dexamethasone pharmacokinetics in human inner ear perilymph using computer simulations

目的:应用计算机模拟方法研究地塞米松鼓室给药途径在人内耳外淋巴液的药物动力学。方法:应用高效液相色谱分析技术,研究地塞米松鼓室给药途径在豚鼠内耳外淋巴液的药物动力学;以此为客观基础,在计算机耳蜗液模拟软件上摸索出最合适的实验模拟参数,模拟地塞米松鼓室给药途径不同用药方案时人内耳外淋巴液的药物浓度。结果:豚鼠鼓室注射0.5%地塞米松150μl后,地塞米松在豚鼠外淋巴液中的药物消除半衰期T1/2K是(2.918±0.089)h,峰浓度C(max)是(231.25±6.89)μg/L。最佳模拟参数是地塞米松磷酸钠的浓度5 000 g/L(0.5%),分子量516,扩散系数为0.693 9×10-5cm2/s,圆窗膜的通透性为2.2×10-11cm/s,药物在外淋巴液半衰期为175 min,前庭阶-鼓阶交换半衰期为45 min。0.5%地塞米松在人中耳分别存留15、30、60、120 min后内耳外淋巴液药物浓度峰值C(max)分别为32.8、64.31、122.6、203.3μg/L;曲线下面积AUC分别为116.5、229.1、423.6、759.2μg/(h.L)。0.5%、1%、2%、4%不同浓度地塞米松在人中耳存留30 min内耳外淋巴液药物浓度峰值C(max)分别为64.3、127.3、255.4、575.6μg/L。曲线下面积AUC分别为229.1、462.8、920.5、1 525.2μg/(h.L)。结论:建立了一套研究人内耳药物动力学的计算机模拟方法,为以后内耳药物动力学的研究打下基础。随着药物在中耳存留时间的延长,内耳外淋巴液药物浓度峰值C(max)与曲线下面积AUC逐渐升高。随着药物浓度的增加,内耳外淋巴液药物浓度峰值C(max)与曲线下面积AUC逐渐升高。

Objective：To study the dexamethasone pharmacokinetics of human inner ear perilymph under different drug administration using computer simulations.Method：The dexamethasone pharmacokinetics in guinea pigs inner ear perilymph under an intratympanic application with high-performance liquid chromatography.Dexamethasone pharmacokinetics in the guinea pigs cochlear fluid were simulated with a computer model,the Washington University Cochlear Fluids Simulator,version 1.6 and the best Simulations parameters to the experimental data could be obtain.With best Simulations parameters based on the experimental data,seven kinds application protocols were designed for human inner ear perilymph.Result：After an intratympanic application dose of 0.5% dexamethasone 150ml in guinea pigs,the T1/2K was（2.918±0.089）h,and Cmax was（231.25±6.89）μg/L.The best Simulations parameters were that concentration of the dexamethasone 21-Phosphate disodium salt was 0.5% and the formula weight was 516,as well as drug diffusion coefficient was 0.693 9×10-5cm2/s and round window permeability was 2.2×10-11cm/s while drug clearance half time was 175 minutes and scala tympaniscala vestibuli communication was 45minutes.After an intratympanic application dose of 0.5% dexamethasone 500 mL,which the applied drug stayed in contact with the round window membrane for 15,30,60 and 120 minutes,the Cmax was 32.8,64.3,122.6 and 203.3 μg/L and the AUC was 116.5,229.1,423.6 and 759.2 μg/（h·L）,respectively.After an intratympanic application dose of 0.5%,1%,2% and 4% dexamethasone 500 ml,which the applied drug stayed in contact with the round window membrance for 30minutes respectively,the Cmax was 64.3,127.3,255.4 and 575.6 μg/L respectively and the AUC was 229.1,462.8,920.59 and 1 525.2 μg/（h·L）,respectively.Conclusion：The dexamethasone harmacokinetics in human inner ear perilymph by computer simulations was reported.As the time contact with the round window membrance increased,the inner ear perilymph concentration of dexamethasone increased.As the concentration of dexamethasone increased,the inner ear perilymph concentration of drug increased.