The pharmacokinetics and pharmacodynamic response to prednisolone were examined in dietary-induced obese rats and matched controls. Pharmacokinetic parameters were examined in absolute and weight normalized terms. After an i.v. dose (range, 4.0-6.3 mg/kg) of prednisolone adjusted to achieve similar initial prednisolone plasma concentrations, the time course of glucocorticoid receptors in hepatic cytosol and hepatic tyrosine aminotransferase (TAT) activity were examined. Plasma prednisolone concentrations declined biexponentially with time. Mean (S.D.) for prednisolone plasma clearance normalized for total body mass (TBM) was 2.3 (0.9) liters/hr/kg in normal rats and 2.7 (0.7) liters/hr/kg in obese rats. The volume of distribution at steady-state averaged 0.82 (0.46) liters/kg of TBM in normal rats vs. 1.08 (0.40) liters/kg of TBM in obese rats. Base-line receptor levels for obese rats were 53% higher than control levels. A model to describe simultaneously kinetics and receptor-mediated dynamics was used to analyze the data and obtain estimates for the efficiency of TAT induction. This efficiency parameter in obese rats was 22% of controls, reflecting the innate degree of diminished TAT response. This decreased response in obese animals may indicate a need for joint pharmacokinetic/dynamic considerations in dosing obese individuals with corticosteroids.