Pharmacokinetics of 3 prednisolone prodrugs. Evidence of therapeutic inequivalence in renal transplant patients with rejection.

Renal allograft rejections are often treated with high doses of prednisone or prednisolone. The solubility of the biologically active prednisolone is poor. Therefore prednisolone is given i.v. as prednisolone disodium phosphate (prednisolone phosphate) or as prednisolone sodium tetrahydrophthalate (prednisolone phthalate). The time course of hydrolysis of high doses of these prodrugs and the reduction of high doses of oral prednisone into prednisolone has not been investigated. Therefore 10 patients treated for acute rejection were given, on 3 occasions, oral prednisone, i.v. prednisolone phosphate, or i.v. prednisolone phthalate in equimolar doses corresponding to 7 mg/kg of prednisolone. Blood samples were collected over a 24-hr period. Measurements were performed by high-performance liquid chromatography and equilibrium dialysis. The time to peak, the peak concentrations, and the area under the plasma-concentration-vs.-time curve (AUC) of prednisone and of unbound prednisolone were calculated. In all patients the hydrolysis of the prednisolone phosphate ester was faster than that of the prednisolone phthalate ester. The mean (+/- SD) peak concentrations of unbound prednisolone were higher after i.v. prednisolone phosphate (18.5 +/- 3.4 micrograms/ml) than after i.v. prednisolone phthalate (2.9 +/- 0.5 micrograms/ml) or after oral prednisone (3.1 +/- 0.8 micrograms/ml), (P less than 0.001). The mean AUCs of unbound prednisolone were 2324 +/- 683 micrograms/ml/min from prednisolone phosphate, 1209 +/- 324 micrograms/ml/min from prednisolone phthalate, and 1584 +/- 556 micrograms/ml/min from oral prednisone. The AUCs of prednisolone from i.v. prednisolone phosphate (P less than 0.001) or from oral prednisone (P less than 0.005) were higher than from i.v. prednisolone phthalate.(ABSTRACT TRUNCATED AT 250 WORDS)