Nonlinear plasma protein binding and haemodialysis clearance of prednisolone

The impact of nonlinear plasma protein binding of a drug on its removal by haemodialysis has been quantified. Prednisolone 10-100 mg was given i.v. to 10 renal transplant patients on haemodialysis for acute tubular necrosis. Dialysate and afferent and efferent blood samples were collected simultaneously in 67 instances. Total and unbound prednisolone in plasma and its total concentration in blood and dialysate were assessed by high performance liquid chromatography and equilibrium dialysis. The amount of prednisolone lost, as measured directly in the dialysate (21.8 +/- 4.4 micrograms/min, mean +/- SE), was predictable from the afferent-efferent blood concentration differences (20.1 +/- 4.8 micrograms/min), but not from measurements of total afferent-efferent prednisolone concentrations in plasma (13.1 +/- 3.0 micrograms/min). The amount of prednisolone lost in the dialysate increased linearly with unbound (r2 = 0.96) and hyperbolically with the total prednisolone concentration in plasma. The latter hyperbolic relationship is adequately described by the equation for nonlinear plasma protein binding, using the affinity and capacity constants of albumin and transcortin for prednisolone (r2 = 0.98). Thus, the haemodialysis clearance of total prednisolone is concentration-dependent, while the clearance of unbound prednisolone is constant (76 ml/min). Free clearance values or measurements of afferent-efferent blood concentrations are mandatory for a drug showing nonlinear plasma protein binding in order to predict the amount lost in the dialysate.