A compartmental model of hepatic disposition kinetics: 1. Model development and application to linear kinetics

被引:21
作者
Anissimov, YG [1 ]
Roberts, MS [1 ]
机构
[1] Univ Queensland, Princess Alexandra Hosp, Dept Med, Woolloongabba, Qld 4102, Australia
基金
英国医学研究理事会;
关键词
compartmental model; dispersion model; hepatic elimination; inverse Gaussian distribution; secondary vascular compartment; hepatic disposition;
D O I
10.1023/A:1019703607647
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The conventional convection-dispersion model is widely used to interrelate hepatic availability (F) and clearance (Cl) with the morphology and physiology of the liver and to predict effects such as changes in liver blood flow on F and Cl. The extension of this model to include nonlinear kinetics and zonal heterogeneity of the liver is not straightforward and requires numerical solution of partial differential equation, which is not available in standard nonlinear regression analysis software. In this paper, we describe an alternative compartmental model representation of hepatic disposition (including elimination). The model allows the use of standard software for data analysis and accurately describes the outflow concentration-time profile for a vascular marker after bolus injection into the liver. In an evaluation of a number of different compartmental models, the most accurate model required eight vascular compartments, two of them with back mixing. In addition, the model includes two adjacent secondary vascular compartments to describe the tail section of the concentration-time profile for a reference marker. The model has the added flexibility of being easy to modify to model various enzyme distributions and nonlinear elimination. Model predictions of F, MTT, CV2, and concentration-time profile as well as parameter estimates for experimental data of an eliminated solute (palmitate) are comparable to those for the extended convection-dispersion model.
引用
收藏
页码:131 / 156
页数:26
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