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,\({{\bar x}}\) ± 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 (r 2=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 (r 2=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.
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Abbreviations
- CBa :
-
Afferent blood concentration [ng/ml]
- CBe :
-
Efferent blood concentration [ng/ml]
- CD :
-
Dialysate concentration [ng/ml]
- CPa :
-
Afferent plasma concentration [ng/ml]
- CPaFree :
-
Free concentration of prednisolone in afferent plasma [ng/ml]
- CPe :
-
Efferent plasma concentration [ng/ml]
- CAPA :
-
Binding capacity of albumin [µg%]
- CAPT :
-
Binding capacity of transcortin [µg%]
- ClB :
-
Blood clearance [ml/min]
- ClFree :
-
Free plasma clearance [ml/min]
- ClP :
-
Plasma clearance [ml/min]
- Ha :
-
Haematocrit in afferent blood
- He :
-
Haematocrit in efferent blood
- K:
-
Partition coefficient between red blood cells and plasma
- KDA :
-
Dissociation constant of albumin (M/L)
- KDT :
-
Dissociation constant of transcortin (M/L)
- QB :
-
Blood flow [ml/min]
- QD :
-
Dialysate flow [ml/min]
- QF :
-
Flow of ultrafiltrate [ml/min]
- t1 :
-
First sampling time point after haemodialysis started
- t2 :
-
Last sampling time point before haemodialysis was discontinued
- ZDdi :
-
Loss of prednisolone in the dialysate by diffusion [µg/min] (“Z” indicates calculated for each sampling time point)
- \({{\bar Z}}\) Ddi :
-
Mean loss of prednisolone in the dialysate by diffusion [µg/min] (“\({{\bar Z}}\)” indicates calculated for the entire haemodialysis period)
- ZDtot :
-
Total amount of prednisolone recovered in the dialysate [µg/min]
- \({{\bar Z}}\) Dtot :
-
Mean total amount of prednisolone recovered in the dialysate [µg/min]
- ZDu :
-
Loss of prednisolone in the dialysate by ultrafiltration [µg/min]
- \({{\bar Z}}\) Du :
-
Mean loss of prednisolone in the dialysate by ultrafiltration [µg/min]
- ZcB :
-
Amount of prednisolone lost in the dialysate calculated from afferent-efferent blood concentrations [µg/min]
- \({{\bar Z}}\) cB :
-
Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent blood concentrations [µg/min]
- ZcP :
-
Amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations [µg/min]
- \({{\bar Z}}\) cP :
-
Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations [µg/min]
- ZcPK :
-
Amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations corrected by the partition coefficient [µg/min]
- \({{\bar Z}}\) cPK :
-
Mean amount of prednisolone lost in the dialysate calculated from afferent-efferent plasma concentrations corrected for the partition coefficient [µg/min]
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Abstract presented to the American Society of Nephrology, Washington, 1981
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Frey, F.J., Gambertoglio, J.G., Frey, B.M. et al. Nonlinear plasma protein binding and haemodialysis clearance of prednisolone. Eur J Clin Pharmacol 23, 65–74 (1982). https://doi.org/10.1007/BF01061379
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DOI: https://doi.org/10.1007/BF01061379