Prednisolone clearance at steady state in man.

The present study was undertaken to determine whether prednisolone exhibits dose-dependent kinetics in man. Ten normal volunteers were infused to steady state over a 7-h period at a low (5.5 microgram/h . kg) and a high (64 microgram/h . kg) rate with prednisolone. Steady state prednisolone levels differed by a factor of 5 [91 +/- 25 and 437 +/- 116 ng/ml (mean +/- SD)] when the infusion rate was increased 12-fold, indicating a marked increase in the clearance of total prednisolone with increasing dose (the ratio of clearances, high to low dose, was 2.47 +/- 0.29). The fraction of unbound prednisolone increased from 0.12 +/- 0.02 to 0.24 +/- 0.02 with increasing dose. Since the increase in the free fraction (2-fold change) was not as great as the increase in the total prednisolone clearance, there was a slight but significant (P less than 0.05) increase in the apparent clearance of unbound prednisolone (ratio of apparent unbound clearances, high to low dose, was 1.29 +/- 0.24). The interconversion between prednisolone and prednisone appears to approach a maximum prednisone concentration, as was noted previously by us in dogs. In humans, we found this maximum prednisone concentration to be 52 ng/ml when prednisolone is infused. Therefore, the ratio of concentrations, prednisolone to prednisone, also increased with increasing prednisolone dose. These results indicate that prednisolone exhibits dose- and concentration-dependent kinetics and that the great majority of the change in kinetics may be attributed to saturable protein binding of prednisolone. Although there is an increase in the apparent clearance of unbound prednisolone with increasing concentrations, these results are confounded by the interconversion process between prednisone and prednisolone.