Tissue distribution of prednisolone in the rabbit

The tissue distribution and kinetics of prednisolone disposition were examined in the rabbit under steady-state conditions. The steroid was infused to attain a range of plasma (362-4528 ng/ml) and tissue concentrations of pharmacologic interest. Blood components and various tissues were analyzed for prednisolone and its major metabolite, prednisone, by high-performance liquid chromatography. Unbound prednisolone was measured in plasma (percentage of binding = 72-82%) by equilibrium dialysis and tissue binding was calculated from tissue/unbound plasma distribution ratios (K(p)) and fractional water content. The small intestine (K(p) = 6.65), heart (2.92), kidney (2.91), lung (2.86), skeletal muscle (1.54) and spleen (1.16) exhibited linear K(p) values and percentage of tissue binding. Red cell content reflected unbound prednisolone in plasma. Liver uptake (K(p) = 0.38-4.47) was nonlinear with apparent tissue binding ranging from less than 59 to 84%. Slight nonlinearity occurred in prednisolone-prednisone interconversion with the liver, kidney and spleen accounting for prednisone formation. Renal clearance of prednisolone was small (6-9% of total clearance), but appreciable steroid concentrations in the bile and small intestine indicate probable enterohepatic cycling. The steady-state total and unbound plasma clearances of prednisolone were similar to those from single-dose studies. Prednisolone-prednisone interconversion and enterohepatic cycling affect the steady-state volume of distribution generated from single-dose studies as the body content/plasma concentration measure of steady-state volume of distribution is about one-half of that estimated conventionally from plasma disposition curves. These studies demonstrate appreciable prednisolone uptake by tissues of clinical importance and indicate the limitations in use of simple models to depict the pharmacokinetics of prednisone and prednisolone.