METABOLITE MEAN TRANSIT TIMES IN THE LIVER AS PREDICTED BY VARIOUS MODELS OF HEPATIC ELIMINATION

Predicted area under curve (AUC), mean transit time (MTT) and normaliz ed variance (CV2) data have been compared for parent compound and gene rated metabolite following an impulse input into the liver, Models stu died were the well-stirred (tank) model, tube model, a distributed tub e model, dispersion model (Danckwerts and mixed boundary conditions) a nd tanks-in-series model. It is well known that discrimination between models for a parent solute is greatest when the parent solute is high ly extracted by the liver. With the metabolite, greatest model differe nces for MTT and CV2 occur when parent solute is poorly extracted. In all cases the predictions of the distributed tube, dispersion, and tas ks-in-series models are between the predictions of the rank and tube m odels. The dispersion model with mixed boundary conditions yields iden tical predictions to those for the distributed tube model (assuming an inverse gaussian distribution of tube transit times). The dispersion model with Danckwerts boundary conditions and the tanks-in series mode ls give similar predictions to the dispersion (mixed boundary conditio ns) and the distributed tube. The normalized variance for parent compo und is dependent upon hepatocyte permeability only within a distinct r ange of permeability values. This range is similar for each model but the order of magnitude predicted for normalized variance is model depe ndent. Only for a one-compartment system is the MIT for generated meta bolite equal to the sum of MTTs for the parent compound and preformed metabolite administered as parent.