Altered Pharmacokinetics of Prednisolone and Cortisol Suppression During Oral Prednisolone Therapy in Patients with Nephrotic Syndrome

Abstract

Background : Steroid preparation exerts its pharmacological effect through the binding of the free unbound fraction to its receptor. However, in patients with nephrotic syndrome, the plasma protein concentration fluctuates, which affects the ratio of bound versus unbound steroid. We investigated the plasma pharmacokinetics of prednisolone administered to patients with nephrotic syndrome through their disease course. Also the suppression of endogenous cortisol during prednisolone therapy was studied. Methods : Fifteen patients(aged 16―75 years, nine minimal change group, four membranous nephropathy, two lupus nephritis)were studied on one or more occasions over a period of one to nine months during prednisolone treatment. Plasma total concentrations of prednisolone were measured by employing gas chromatography/mass spectrometry simultaneously with endogenous cortisol at several time points on each occasion. Individualized estimation of the patient's kinetic parameters was done by a computer curve fitting of the total plasma prednisolone. Results : Blood sampling at several time points on each occasion made it possible to characterize the intraand inter-individual variability in the pharmacokinetic behavior of prednisolone. There was a negative correlation(r = 0.4676, P = 0.0031)between the prednisolone clearance and plasma albumin concentrations. As the plasma albumin level increases, the area under the plasma total prednisolone concentration-time curve(AUCtotal)increased, whereas the area under the plasma unbound prednisolone concentration-time curve(AUCunbound)decreased. The discrepancy between AUCtotal and AUCunbound was observed at the plasma albumin concentration below 3.0 g/dl. The endogenous cortisol concentration immediately declined after administering the first prednisolone dose. Adrenal suppression is less in patients in whom prednisolone was administered only in the morning than in patients in whom prednisolone was administered in two or three divided doses. Conclusion : Concentration of free unbound prednisolone decreases as the plasma albumin concentration is recovered. It is recommended that the dosage reduction be started after the plasma albumin concentration is normalized and stabilized(above 3.0 g/dl). In addition administration of prednisolone once daily in the morning is recommended to prevent adrenal suppression. 原 著