Albumin is known to affect the intrinsic clearance of many compounds in the isolated perfused rat liver, but little is known of its effect in vivo. The influence of decreased albumin concentrations on clearance of unbound prazosin and intrinsic clearance of prazosin was therefore studied in vivo in rats that had undergone plasmapheresis. An approximate 30% reduction in the plasma albumin concentration was achieved in animals not given plasma expanders and an approximate 50% reduction was achieved in animals given Ficol 70 as a plasma expander. No differences were seen in the intrinsic clearances or in the clearances of unbound prazosin between control animals and plasmapheretic animals. The reason for this lack of effect is apparent from parallel studies in isolated perfused rat livers. An increase in the clearance of unbound prazosin of 27% was seen when the albumin concentration was increased from 0 to 30 microM, and of 49% when the concentration of albumin was increased to 90 microM, with no further increase at higher albumin concentration. These results, therefore, suggest that changes in the albumin plasma concentrations normally encountered clinically may have little effect on the intrinsic elimination of drugs.