Disposition of prednisone and prednisolone in the perfused rabbit liver: Modeling hepatic metabolic processes

Abstract

The livers of 15 rabbits were perfused in situ with prednisone (PO) or prednisolone (POH) over a wide range of steady state concentrations, resulting in multiple experimental measurements per organ. Linearity of extraction, an apparent lack of oxidative conversion, and marked preference for the reduction of PO to POH was observed. Predictions of hepatic tissue concentrations were made using both the well-stirred and parallel-tube model approximations. Glucocorticoid disposition across the liver was described by a series of differential equations. Discrimination between the two models was accomplished by examining the effects of changes in flow rate upon the availability of the highly extracted drug PO. The well-stirred model very closely predicted the observed changes in availability of PO, whereas the parallel-tube model provided poor predictions. The intrinsic clearances of interconversion and elimination of PO and POH were subsequently calculated by population analysis using NONMEM. This method assumed the well-stirred model and resulted in intrinsic clearance estimates of 26 ml/min for the elimination of POH, 157 ml/min for reductive conversion of PO to POH, and 205 ml/min for the irreversible elimination of PO. A mechanism of intrahepatic disposition of these glucocorticoids was proposed using well-stirred model predictions of hepatic drug concentrations, the perfusion rate limitation to drug transport, and the assumption of no oxidative interconversion of POH to PO. In this case, the capacity for reduction of PO to POH approaches the elimination clearance of PO and the elimination of PO is about 13 times greater than the elimination clearance of POH.