Pharmacokinetic modeling of reversible interconversion between prednisolone and prednisone

Pharmacokinetics of prednisolone and prednisone undergoing reversible interconversion were analyzed from the model including this metabolic process. Blood samples were drawn serially upto 12 hours after I.V. bolus injection of 1 mg/kg prednisolone sodium phosphate and prednisone into 8 dogs as a crossover manner. Plasma concentrations of those two steroids were simultaneously measured with the method of HPLC. After injection, plasma concentrations of administered prednisolone and prednisone were declined with a biexponential pattern and their metabolic partner was rapidly formed. Plasma concentrations of those metabolites were decayed in parallel with their parent steroids throughout the elimination phase. Apparent clearances of prednisolone and prednisone were 11.1 ± 2.0 ml/min/kg and 45.9 ± 6.4 ml/min/kg, and they were underestimated by 29.4% and 33.6% compared to their real clearances (15.7 ± 4.4 and 69.2 ± 17.7 ml/min/kg) estimated using reversible interconversion model. Apparent volume of distribution of prednisolone (1.32 ± 0.43 L/kg) and prednisone (4.81 ± 2.75 L/kg) were overestimated by 53.5 and 52.7% and were compared to the real volumes (0.86 ± 0.30 and 3.15 ± 2.13 L/kg). Mean residence time of prednisolone (2.0 ± 0.6 1 h) and prednisone (1.74 ± 0.74 h) were much longer than the real sojourn time (0.93 ± 0.26 and 0.88 ± 0.54 h). Essential clearances in the reversible interconversion were greater as following orders: Cl₂₁ (44.3 ml/min/kg) > Cl₂₀ (24.2 ml/min/kg) > Cl₁₂ (7.9 ml/min/kg) > Cl₁₀ (7.8 ml/min/kg). Estimated mean values of RF, EE, %X¹(ss) and RHO²₁ were 0.31 ± 0.10, 1.49 ± 0.23, 69.3 ± 16.7% and 0.65 ± 0.10, respectively. These results suggested that true pharmacokinetic parameters estimated from the model including reversible interconversion were significantly different from the apparent parameters estimated from the conventional mamillary model, and disposition of these two steroids seemed to be well explained by the model including reversible interconversion.