The absence of effect of azathioprine on prednisolone pharmacokinetics following maintenance prednisone doses in kidney transplant patients.

Kidney transplant patients receive chronic prednisone and azathioprine for immunosuppression. However, the effect of azathioprine on prednisolone pharmacokinetics has not been determined in this population. Total and unbound prednisolone concentrations were determined, using high performance liquid chromatography and equilibrium dialysis, in eight kidney transplant patients following their usual oral maintenance dose of prednisone alone and concomitantly with their usual dose of azathioprine. The results showed no significant differences between the two groups in estimates of prednisolone plasma protein binding parameters and peak time, peak concentration, mean input time, clearance/F, volume of distribution/F, or half-life (t 1/2), using total or unbound prednisolone concentrations. Thus, the concomitant administration of azathioprine does not appear to alter the bioavailability or elimination of prednisolone at these doses.

Disposition of total and unbound prednisolone in renal transplant patients receiving anticonvulsants.

Kidney transplant patients receiving phenytoin or phenobarbital may have decreased graft survival. These drugs have been shown to enhance the metabolism of glucocorticoids. We determined the disposition of total and unbound prednisolone in six stable kidney transplant patients receiving prednisone for immunosuppression and phenytoin or phenobarbital for a seizure disorder. Six similar patients not on anticonvulsants served as controls. A single intravenous dose of prednisolone was administered, and plasma samples were analyzed for prednisolone using a high-performance liquid chromatographic assay. Equilibrium dialysis was used to determine unbound prednisolone concentrations. Pharmacokinetic analysis showed that the half-life of prednisolone was shorter in the anticonvulsant group compared to the controls, based on both total (2.3 +/- 0.4 vs. 3.4 +/- 0.2 hr (SD), P less than 0.01) and unbound (1.7 +/- 0.3 vs. 2.4 +/- 0.2 hr, P less than 0.01) concentrations. Total drug clearance was 10.4 +/- 2.8 liters/hr (0.171 +/- 0.087 liters/hr X kg) in the anticonvulsant group versus 7.2 +/- 1.2 liters/hr (0.100 +/- 0.014 liters/hr X kg) in the controls (P less than 0.05). Unbound prednisolone clearance was 57.2 +/- 12.1 versus 46.4 +/- 8.7 liters/hr (P greater than 0.05) and for weight-corrected estimates 0.886 +/- 0.224 liters/hr X kg versus 0.644 +/- 0.115 liters/hr X kg (P less than 0.05) in the two groups, respectively. Thus, the disposition of prednisolone is altered by anticonvulsants in kidney transplant patients and may require dose alteration.

Prednisone and prednisolone bioavailability in renal transplant patients.

Prednisone and prednisolone are drugs with the potential for therapeutic inequivalence due to bioavailability problems. The objective of our study was to compare the systemic bioavailability of prednisolone from oral prednisone and prednisolone. Nine kidney transplant patients receiving prednisone (12.5 to 22.5 mg per day) were administered, in a randomized fashion, the same dose of oral prednisone (Deltasone), oral prednisolone (Delta-cortef) and intravenous prednisolone (Hydeltrasol). Prednisolone and prednisone levels were measured using a specific high-pressure liquid chromatographic assay. Since prednisolone exhibits dose-dependent pharmacokinetics because of nonlinear plasma protein binding, bioavailability from oral prednisone and oral prednisolone, compared to the intravenous dose, was 84.5 +/- 17.8% and 95.5 +/- 17.6% using unbound drug concentrations. These differences were not statistically significant. Furthermore, no significant differences were observed between the two oral formulations in peak prednisolone levels, time of peak levels or half-life using either total or unbound drug concentrations. The results from our study indicate that both of the oral preparations tested provide similar bioavailability of active prednisolone and the conversion of prednisone to prednisolone occurs rapidly.