Dose‐dependent prednisolone kinetics

Kinetic data for prednisolone and prednisone have been determined following oral administration of prednisolone over a dosage range of 5 to 200 mg in 43 subjects. Intravenous studies have been performed at 20 mg and 100 mg in 3 subjects. At all dosage levels the elimination t½β for prednisolone remained constant (t½β 3.5 ± 0.2 hr [20 mg], t½β 3.7 ± 0.1 hr [100 mg] mean ± SEM). For prednisolone, there was a linear relationship between dose and AUC 0→∞ and C max up to a dose of 20 mg, but above this level AUC0 0→∞ and C max demonstrated a less rapid increase as the dose increased. The prednisone AUC 0→∞ . remained a constant proportion, 26 ± 2%, of the prednisolone AUC 0→∞ at all dosage levels. Bioavailability of prednisolone was 98.5 ± 4%. There was a constant amount of prednisolone bound to cortisol‐binding globulin (CBG) (145 ± 16 ng/ml) and as a proportion of the remaining serum prednisolone, the free remained at 14 ±2% and non‐CBG protein‐bound prednisolone at 86 ± 2% over the whole dosage range. The intravenous studies demonstrated a significant difference in the volume of distribution of prednisolone as the dose changed from 20 mg (V d 58 ±4 L) to 100 mg (V d 90 ± 6 L). Since it has been demonstrated that bioavailability, serum protein binding, prednisone‐prednisolone interconversion, and t½β remained constant over this dosage range, the altered V d may account for the nonlinear relationship between AUC and dose.