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Comparison of the gamma-Pareto convolution with conventional methods of characterising metformin pharmacokinetics in dogs.
Journal of Pharmacokinetics and Pharmacodynamics ( IF 2.5 ) Pub Date : 2019-12-21 , DOI: 10.1007/s10928-019-09666-z
Carl A Wesolowski 1 , Surajith N Wanasundara 1 , Paul S Babyn 1 , Jane Alcorn 2
Affiliation  

A model was developed for long term metformin tissue retention based upon temporally inclusive models of serum/plasma concentration (\( C \)) having power function tails called the gamma-Pareto type I convolution (GPC) model and was contrasted with biexponential (E2) and noncompartmental (NC) metformin models. GPC models of \( C \) have a peripheral venous first arrival of drug-times parameter, early \( C \) peaks and very slow washouts of \( C \). The GPC, E2 and NC models were applied to a total of 148 serum samples drawn from 20 min to 72 h following bolus intravenous metformin in seven healthy mongrel dogs. The GPC model was used to calculate area under the curve (AUC), clearance (\( CL \)), and functions of time, f(t), for drug mass remaining (M), apparent volume of distribution (\(V_{d}\)), as well as \(t_{1/2}\ f(t)\) for \( C \), \( M \) and \(V_{d}\). The GPC models of \( C \) yielded metformin \( CL \)-values that were 84.8% of total renal plasma flow (RPF) as estimated from meta-analysis. The GPC \( CL \)-values were significantly less than the corresponding NC and E2 \( CL \)-values of 104.7% and 123.7% of RPF, respectively. The GPC plasma/serum only model predicted 78.9% drug \( M \) average urinary recovery at 72 h; similar to prior human urine drug \( M \) collection results. The GPC model \(t_{1/2}\) of \( M \), \( C \) and \(V_d\), were asymptotically proportional to elapsed time, with a constant limiting \(t_{1/2}\) ratio of M/C averaging 7.0 times, a result in keeping with prior simultaneous \( C \) and urine \( M \) collection studies and exhibiting a rate of apparent volume growth of \(V_d\) that achieved limiting constant values. A simulated constant average drug mass multidosing protocol exhibited increased \(V_d\) and \(t_{1/2}\) with elapsing time, effects that have been observed experimentally during same-dose multidosing. The GPC heavy-tailed models explained multiple documented phenomena that were unexplained with lighter-tailed models.

中文翻译:

γ-帕累托卷积与表征狗中二甲双胍药代动力学的常规方法的比较。

基于具有时间幂函数尾巴的血清/血浆浓度(\(C \))的时间包容性模型,开发了一种用于长期二甲双胍组织滞留的模型,称为I型伽马-帕累托I卷积(GPC)模型,并与双指数(E2)进行了对比。 )和非隔室(NC)二甲双胍模型。\(C \)的GPC模型具有药物时间参数的外周静脉先到达,早期(\ C \)峰值和非常慢的\(C \)洗脱时间。将GPC,E2和NC模型应用于推注静脉注射二甲双胍后20分钟至72 h的7只健康杂种狗的148个血清样品。GPC模型用于计算曲线下的面积(AUC),间隙(\(CL \))以及时间函数ft),剩余药物质量(M),表观分布体积(\(V_ {d} \))以及\(t_ {1/2} \ f(t )\)表示\(C \)\(M \)\(V_ {d} \)。根据荟萃分析估计,\(C \)的GPC模型产生的二甲双胍\(CL \)值为肾脏总血浆流量(RPF)的84.8%。GPC \(CL \)值显着小于相应的NC和E2 \(CL \)值,分别为RPF的104.7%和123.7%。仅GPC血浆/血清模型预测药物占78.9%(M)72小时的平均尿量恢复;与先前的人类尿液药物(M)收集结果相似。该GPC模型\(T_ {1/2} \)\(M \) \(C \)\(V_D \),分别为渐近正比于经过的时间,以恒定的限制\(T_ {1/2 } \)平均M / C比为7.0倍,这与先前同时进行的\(C \)和尿液\(M \)收集研究保持一致,并且表现出表观体积(\ _V_d \)的增长率达到了极限常数值。模拟的恒定平均药物质量多剂量方案显示出增加的\(V_d \)\(t_ {1/2} \)随着时间的流逝,在相同剂量的多次给药过程中已通过实验观察到了这种效果。GPC重尾模型解释了多种记录的现象,而轻尾模型则无法解释。
更新日期:2019-12-21
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