Altered plasma protein-binding of prednisolone in patients with the nephrotic syndrome.

Abstract

Prednisolone binds in plasma to both albumin and transcortin. Since altered concentrations of plasma proteins change capacity and association constants of the drug-protein complex and thus influence the disposition of the drug, the kinetics of prednisolone following oral prednisone and intravenous (IV) prednisolone were studied in ten nephrotic patients and in 12 healthy volunteers. Compared to normal volunteers, nephrotic patients had significantly higher mean (+/- SD) association constants for the albumin-prednisolone complex (4.20 +/- 2.10 X 10(3) M-1 v 2.26 +/- 0.46 X 10(3) M-1, P less than 0.005) and tended to have higher association constants for the transcortin-prednisolone complex. Following the IV administration of prednisolone and the oral administration of prednisone, nephrotic patients exhibited lower total plasma concentrations of prednisolone than did normal volunteers. The difference was attributable to lower albumin-bound and/or transcortin-bound, but not unbound, concentrations of prednisolone in plasma. The mean prednisolone bioavailability from oral prednisone was not different between nephrotic patients and controls. When calculated with reference to total prednisolone concentrations in plasma, the mean nonrenal clearance rate, but not the mean renal clearance rate, was higher in the nephrotic patients than in the controls (2.63 +/- 0.61 mL/min/kg v 1.85 +/- 0.33 mL/min/kg, P less than 0.005). Compared to normal volunteers, patients with the nephrotic syndrome had lower renal clearance rates of unbound prednisolone when prednisolone was given intravenously (1.58 +/- 0.88 mL/min/kg v 2.89 +/- 0.89 mL/min/kg, P less than 0.005) or when prednisone was given orally (1.18 +/- 0.86 mL/min/kg v 2.80 +/- 1.13 mL/min/kg, P less than 0.005). Nephrotic patients had lower ratios of unbound prednisolone clearance/creatinine clearance (fractional excretion) after IV prednisolone (1.50 +/- 0.81 v 2.27 +/- 0.49, P less than 0.025) or after oral prednisone (1.07 +/- 0.60 v 2.12 +/- 0.77, P less than 0.005) than the controls. Since these fractional excretion values of unbound prednisolone exceeded one, there must be glomerular filtration of prednisolone bound to plasma proteins and/or tubular secretion of prednisolone. This study indicates that the nephrotic dysproteinemia changes the binding of prednisolone to plasma proteins not only in point of quantity, but also in point of quality, and alters the disposition of prednisolone.