Shaik Mastan, Shaik Shabana, Kilari Eswar Kumar
Troikaa Pharmaceuticals Ltd, Medical Services, Satyamarg, Bodakdev, Ahmedabad Gujarat, India.
Research Consultant, Venkata Reddy Nagar, Nellore, Andhra Pradesh, India.
Biopharm Drug Dispos. 2018 May;39(5):265-274. doi: 10.1002/bdd.2132.
Gliclazide is a second-generation sulphonylurea drug widely used in the treatment of type 2 diabetes. However, there is no single report to describe the population pharmacokinetics of gliclazide in animal models. This study was aimed to evaluate the population pharmacokinetics (PK) of gliclazide in normal and alloxan-induced diabetic rabbits using nonlinear mixed effects modeling. A total of 90 New Zealand white rabbits were administered with three doses (4.13, 8.27 and 16.53 mg/kg b.wt) of gliclazide by an oral route. Blood samples were collected up to 24 hr and the gliclazide concentrations in rabbit were determined using the HPLC method. The non-compartmental and classical compartmental PK analyses were performed using Phoenix WinNonlin. Population PK analysis of gliclazide was performed using nonlinear mixed-effects model software NONMEM and Phoenix NLME considering the weight, age, sex, health and dose as covariates. The final population values for clearance (CL), volume of distribution (V) and the absorption rate constant (k ) were 5270 ml/hr, 55700 ml and 0.708 hr , respectively. The inter-individual variability in gliclazide CL, V and k was 16.3%, 14.9% and 26.5%, respectively. There was no significant difference between NONMEM and Phoenix NLME pharmacokinetic results. The visual predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates from this model. This population PK model demonstrated that gliclazide pharmacokinetics is best described by one-compartment model with first-order absorption in rabbits. Body weight is a covariate that significantly influences gliclazide kinetic disposition in rabbits.
格列齐特是一种广泛用于治疗2型糖尿病的第二代磺酰脲类药物。然而，尚无单一报告描述格列齐特在动物模型中的群体药代动力学。本研究旨在使用非线性混合效应模型评估格列齐特在正常和四氧嘧啶诱导的糖尿病兔中的群体药代动力学（PK）。总共90只新西兰白兔通过口服途径给予三剂（4.13、8.27和16.53mg/kg体重）格列齐特。采集血样长达24小时，并使用高效液相色谱法测定兔体内的格列齐特浓度。使用Phoenix WinNonlin进行非房室和经典房室PK分析。考虑体重、年龄、性别、健康状况和剂量作为协变量，使用非线性混合效应模型软件NONMEM和Phoenix NLME进行格列齐特的群体PK分析。清除率（CL）、分布容积（V）和吸收速率常数（k）的最终群体值分别为5270ml/hr、55700ml和0.708hr⁻¹。格列齐特CL、V和k的个体间变异性分别为16.3%、14.9%和26.5%。NONMEM和Phoenix NLME的药代动力学结果之间无显著差异。直观预测检查和自抽样分析证实了该模型参数估计的预测能力、模型稳定性和精度。该群体PK模型表明，格列齐特的药代动力学在兔中最好用具有一级吸收的一室模型来描述。体重是显著影响兔体内格列齐特动力学处置的协变量。
