The aim of the present investigation has been directed towards investigating the functional variability of hepatic arterial and portal venous streams in relation to drug elimination, and to examine their effects on the predictive ability of hepatic models of drug clearance. In single input isolated perfused liver systems, drug availability administered through the hepatic artery, when compared with portal venous administration, was found to be more than 3 and 18 times greater for pethidine and lignocaine respectively. In dual input systems with a constant total flow, drug availability increases linearly for pethidine, and log linearly for lignocaine with increasing hepatic arterial flow contributions. Injections of 15 micron gamma-labelled microspheres in single input systems did not reveal any significant route-dependent difference in its gross intrahepatic distribution nor does it reveal any significant arteriovenous and portovenous shunting channels greater than 15 micron . However, the ratio of the mean transit times of albumin to RBC was found to be significantly lower through the hepatic artery. In dual input systems, linear correlations were obtained when values of this ratio were plotted against increasing hepatic artery flow contributions. With regard to hepatic models of drug clearance, in recirculating portally perfused isolated liver systems, hepatic elimination kinetics of lignocaine and pethidine under perturbations of flow can be better described by the 'well-stirred', instead of the 'parallel-tube' model. However the predictions of "both models failed when single pass, dual input systems were investigated. Attempts at data fitting of the changes in observed effluent lignocaine with changes in total flow suggests that the best fit of observed with predicted data is obtained when the vascular bed is regarded as consisting of two functionally separate 'well-stirred' compartments.
|Date of Award||1982|