Morgan D J, Smallwood R A
Department of Pharmaceutics, Victorian College of Pharmacy, Melbourne, Australia.
Clin Pharmacokinet. 1990 Jan;18(1):61-76. doi: 10.2165/00003088-199018010-00004.
Various pharmacokinetic models, both simple and complex, have been developed to describe the way in which the rate of hepatic elimination of drugs depends on hepatic blood flow, hepatic intrinsic clearance and unbound fraction of drug in blood. A model is necessary because it is not possible to measure the average blood concentration of drug within the liver, i.e. the concentration at the site of drug elimination. However, the predictions of these models can differ markedly for drugs of high hepatic clearance, especially with the oral route of administration. Investigations of the models have mostly involved studies with in vitro experimental preparations, such as isolated perfused livers. While such studies have advanced our understanding of the mechanism of hepatic uptake and elimination processes, the implications for clinical drug usage have been somewhat neglected. Use of one of the available models is necessary for the assessment of the capacity of in vivo hepatic drug metabolism processes (i.e. hepatic intrinsic clearance) and for predicting the effect of increasing dose on blood concentrations of high clearance drugs exhibiting Michaelis-Menten elimination kinetics, especially those that undergo a nonlinear hepatic first-pass effect. Clinically significant differences between the models can occur under these circumstances. A model is also required for quantitative prediction of the effect on blood drug concentrations of changes in hepatic blood flow, hepatic intrinsic clearance or drug-protein binding in blood. It is in predicting these changes that differences of major clinical significance can occur between the models. The greatest differences are seen in predicting the effect for orally administered drugs of changes of hepatic blood flow on blood concentrations, and changes of protein binding on unbound blood concentrations of drug. These changes can result from disease processes, altered physiology (old age or pregnancy), food intake or concomitant administration of other drugs. A model is also required for determining the mechanism by which such clinical changes occur. When considering these effects on hepatic elimination, it is essential to appreciate that the conclusions may depend markedly on the particular model chosen. Until more data on the applicability of the models are obtained in humans, the undistributed sinusoidal and venous equilibrium models, which represent the opposite extremes of behaviour among the available models, should both be used in assessing hepatic drug elimination.
已经开发出各种简单和复杂的药代动力学模型，用于描述药物肝清除率取决于肝血流量、肝内在清除率和血液中药物游离分数的方式。之所以需要一个模型，是因为无法测量肝脏内药物的平均血药浓度，即药物消除部位的浓度。然而，对于高肝清除率的药物，尤其是口服给药途径，这些模型的预测可能会有显著差异。对这些模型的研究大多涉及体外实验制剂的研究，如离体灌注肝脏。虽然这类研究增进了我们对肝脏摄取和消除过程机制的理解，但对临床药物使用的影响在一定程度上被忽视了。使用现有的模型之一对于评估体内肝脏药物代谢过程的能力（即肝内在清除率）以及预测增加剂量对表现出米氏消除动力学的高清除率药物血药浓度的影响是必要的，尤其是那些经历非线性肝首过效应的药物。在这些情况下，模型之间可能会出现具有临床意义的差异。还需要一个模型来定量预测肝血流量、肝内在清除率或血液中药物与蛋白结合的变化对血药浓度的影响。正是在预测这些变化时，模型之间可能会出现具有重大临床意义的差异。在预测肝血流量变化对口服给药药物血药浓度的影响以及蛋白结合变化对药物游离血药浓度的影响时，差异最为明显。这些变化可能由疾病过程、生理改变（老年或怀孕）、食物摄入或同时服用其他药物引起。还需要一个模型来确定这些临床变化发生的机制。在考虑这些对肝脏消除的影响时，必须认识到结论可能明显取决于所选择的特定模型。在获得更多关于模型在人体适用性的数据之前，应同时使用未分布的正弦和静脉平衡模型来评估肝脏药物消除，这两个模型代表了现有模型中行为的相反极端情况。
