Nonlinear plasma protein binding and haemodialysis clearance of prednisolone

Summary 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 µg/min, ± SE), was predictable from the afferent-efferent blood concentration differences (20.1±4.8 µg/min), but not from measurements of total afferent-efferent prednisolone concentrations in plasma (13.1±3.0 µg/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.Abbreviations Used C_Ba Afferent blood concentration [ng/ml] - C_Be Efferent blood concentration [ng/ml] - C_D Dialysate concentration [ng/ml] - C_Pa Afferent plasma concentration [ng/ml] - C_PaFree Free concentration of prednisolone in afferent plasma [ng/ml] - C_Pe Efferent plasma concentration [ng/ml] - CAP_A Binding capacity of albumin [µg%] - CAP_T Binding capacity of transcortin [µg%] - Cl_B Blood clearance [ml/min] - Cl_Free Free plasma clearance [ml/min] - Cl_P Plasma clearance [ml/min] - H_a Haematocrit in afferent blood - H_e Haematocrit in efferent blood - K Partition coefficient between red blood cells and plasma - KD_A Dissociation constant of albumin (M/L) - KD_T Dissociation constant of transcortin (M/L) - Q_B Blood flow [ml/min] - Q_D Dialysate flow [ml/min] - Q_F Flow of ultrafiltrate [ml/min] - t₁ First sampling time point after haemodialysis started - t₂ Last sampling time point before haemodialysis was discontinued - Z_Ddi Loss of prednisolone in the dialysate by diffusion [µg/min] (Z indicates calculated for each sampling time point) - _Ddi Mean loss of prednisolone in the dialysate by diffusion [µg/min] ( indicates calculated for the entire haemodialysis period) - Z_Dtot Total amount of prednisolone recovered in the dialysate [µg/min] - _Dtot Mean total amount of prednisolone recovered in the dialysate [µg/min] - Z_Du Loss of prednisolone in the dialysate by ultrafiltration [µg/min] - _Du Mean loss of prednisolone in the dialysate by ultrafiltration [µg/min] - Z_cB Amount of prednisolone lost in the dialysate calculated from afferent-efferent blood concentrations [µg/min] - _cB Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent blood concentrations [µg/min] - Z_cP Amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations [µg/min] - _cP Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations [µg/min] - Z_cPK Amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations corrected by the partition coefficient [µg/min] - _cPK Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations corrected for the partition coefficient [µg/min]Abstract presented to the American Society of Nephrology, Washington, 1981