Abstract

The rabbit and human both display nonlinear pharmacokinetics of prednisone (PO) and prednisolone (POH). The in vivo apparent clearances of these compounds increase with dose. To determine whether one source of the kinetic nonlinearity is due to hepatic metabolism, the isolated liver of the rabbit was perfused with widely varying concentrations of both PO and POH in the absence of corticosteroid binding globulin. Both compounds exhibited constant extraction ratios over a wide concentration range, even at concentrations exceeding 100 times those expected in portal venous blood during absorption of orally administered drug. Hepatic extraction of POH averaged 0.49 and that of PO was nearly complete at 0.96. The apparent hepatic blood clearance of POH was about 16 ml/min and that of PO approximated liver blood flow, at 30 ml/min. Furthermore, the liver was predominantly reductive toward these compounds: upon PO perfusion, POH was recovered as about half of the dose of PO administered. POH perfusion yielded no detectable PO in the exiting perfusate. The liver is believed to be the most significant organ involved in glucocorticoid biotransformation. Its capacity to eliminate PO and POH does not appear to be saturable, and greatly favors the pharmacologically active, reduced compound, POH. Hypotheses that attribute the nonlinear pharmacokinetics of PO and POH as partially due to saturable hepatic metabolism may be incorrect. It has been previously assumed that all metabolic organs produce both interconversion products. Since the liver apparently yields no PO (oxidized form), another organ must be responsible for the in vivo oxidation.