Horkovics-Kovats S
Biochemie GmbH, Kundl, Austria.
Arzneimittelforschung. 1999 Oct;49(10):805-15. doi: 10.1055/s-0031-1300506.
A new approach has been developed to determine the factors that influence the balance of drug elimination from the body. This approach is based on 1. a six-compartment-model with compartments connected by different flow rates assuming kinetic processes of first order, 2. on solutions of geometric series and 3. on numerical solutions of a system of non-linear equations. In the model, different ways of drug elimination have been considered: renal, liver and fecal elimination of the drug and its metabolism in the liver. The organs have been characterized by their drug availabilities. Further, the metabolic activity of the liver, the efficiency of drug absorption and re-absorption from the gastrointestinal (GI) tract have been included. This paper identifies three events, characterized by their efficiencies--1. hepatic excretion, 2. elimination of drug from liver into the gall bladder in its non-metabolized form and 3. the re-absorption of the drug from GI tract--as necessary conditions of enterohepatic circulation of (EHC). The product of these efficiencies has been introduced as the efficiency of enterohepatic circulation. Further, the drug bioavailability as a function of the efficiency of EHC is presented. The study shows that--based on the total amounts of non-metabolized drug in urine after p.o. and i.v. administration to animals with and without cannulated bile duct and in the bile of cannulated animals--the efficiency of EHC, bioavailability of the drug, renal and hepatic availability of the drug, metabolic activity of the liver and efficiency of drug absorption and re-absorption from the gut can be determined. Additionally, it has been shown that, depending on the efficiency of enterohepatic circulation, small variabilities in drug pharmacokinetic properties can cause high variance of drug bioavailability. The publication points towards the efficiency of EHC as on a factor that plays a key role in establishing in vitro-in vivo correlation.
一种新的方法已被开发出来，用于确定影响药物从体内消除平衡的因素。该方法基于：1. 一个六室模型，各室通过不同流速相连，假定为一级动力学过程；2. 几何级数的解；3. 一个非线性方程组的数值解。在该模型中，已考虑了药物消除的不同方式：药物的肾排泄、肝排泄和粪便排泄以及其在肝脏中的代谢。各器官已通过其药物可利用性来表征。此外，还纳入了肝脏的代谢活性、药物从胃肠道（GI）的吸收和重吸收效率。本文确定了三个以其效率为特征的事件——1. 肝脏排泄；2. 药物以非代谢形式从肝脏排入胆囊；3. 药物从胃肠道的重吸收——作为肠肝循环（EHC）的必要条件。这些效率的乘积已被引入作为肠肝循环的效率。此外，还给出了作为EHC效率函数的药物生物利用度。该研究表明——基于对有和没有插管胆管的动物口服和静脉注射给药后尿中未代谢药物的总量以及插管动物胆汁中的总量——可以确定EHC的效率、药物的生物利用度、药物的肾和肝可利用性、肝脏的代谢活性以及药物从肠道的吸收和重吸收效率。此外，还表明，取决于肠肝循环的效率，药物药代动力学性质的小变化可导致药物生物利用度的高变异性。该出版物指出EHC的效率是在建立体外-体内相关性中起关键作用的一个因素。
