Comparison of four physiological models for analysis of glucose wash-in curves in the perfused rat liver

Full text: Oxygen diffusion may be involved in the pathogenesis of impaired drug metabolism by the aged (Le Couteur and McLean 1998) and cirrhotic (McLean and Morgan 1991) liver. To measure the barrier for oxygen transfer between the sinusoid and hepatocyte, we developed a carbon monoxide wash-in technique (Le Couteur et al 1999). The modelling of wash-in curves has been investigated much less intensively than multiple indicator dilution experiments, which utilize bolus injection of substrates. To investigate the effectiveness of various physiological models to fit wash-in curves, we performed wash-in experiments on the livers of male Wistar rats perfused in situ and single-pass with Krebs Henseleit buffer. Test perfusate contained 14C-sucrose as the extracellular marker and 3H-glucose. Liver perfusions were performed with background glucose concentrations of 6, 11, 51 or 109 mM. Outflow time-activity curves were analysed using four models. The Vmax and Km, for the influx of glucose were 1.1±0.03 μg/s/ml and 41.1±3.3 mM using the Crone-Renkin early extraction model; 1.4±0.04 μg/s/ml and 36.3±2.6 mM with dispersion model analysis; 1.8±0.1 μg/s/ml and 24.9±4.2 mM using the Goresky distributed model to fit differentiated wash-in curves; and 2.3±0.5 μg/s/ml and 29.3±16.5 mM using compartmental analysis. There was reasonable agreement between the four models and they yielded results that are similar to those reported for glucose uptake in other preparations. The differences between the models probably reflect differences in assumptions about the effects of efflux, mixing of glucose in the compartments and vascular hetereogeneity. The compartmental model that we used previously to examine gas disposition in the perfused liver gave higher estimates for transport than the other three models. Copyright (2001) Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists