Pharmaceutical-grade albumin: impaired drug-binding capacity in vitro.
BACKGROUND
Albumin is the most abundant protein in blood plasma, and due to its ligand binding properties, serves as a circulating depot for endogenous and exogenous (e.g. drugs) compounds. Hence, the unbound drug is the pharmacologically active drug. Commercial human albumin preparations are frequently used during surgery and in critically ill patients. Recent studies have indicated that the use of pharmaceutical-grade albumin is controversial in critically ill patients. In this in vitro study we investigated the drug binding properties of pharmaceutical-grade albumins (Baxter/Immuno, Octapharma, and Pharmacia & Upjohn), native human serum, and commercially available human serum albumin from Sigma Chemical Company.


METHODS
The binding properties of the various albumin solutions were tested in vitro by means of ultrafiltration. Naproxen, warfarin, and digitoxin were used as ligands. HPLC was used to quantitate the total and free drug concentrations. The data were fitted to a model of two classes of binding sites for naproxen and warfarin and one class for digitoxin, using Microsoft Excel and Graphpad Prism.


RESULTS
The drugs were highly bound to albumin (95-99.5%). The highest affinity (lowest K1) was found with naproxen. Pharmaceutical-grade albumin solutions displayed significantly lower drug-binding capacity compared to native human serum and Sigma albumin. Thus, the free fraction was considerably higher, approximately 40 times for naproxen and 5 and 2 times for warfarin and digitoxin, respectively. The stabilizers caprylic acid and N-acetyl-DL-tryptophan used in the manufacturing procedure seem to be of importance. Adding the stabilizers to human serum and Sigma albumin reduced the binding affinity whereas charcoal treatment of the pharmaceutical-grade albumin from Octapharma almost restored the specific binding capacity.


CONCLUSIONS
This in vitro study demonstrates that the specific binding for warfarin and digitoxin is significantly reduced and for naproxen no longer detectable in pharmaceutical-grade albumin. It further shows that the addition of stabilizers may be of major importance for this effect.
Olsen
Harald
H
Central Laboratory, The Norwegian Radium Hospital HF, N-0310 Oslo, Norway. har-ol@online.no
Andersen
Anders
A
Nordbø
Arve
A
Kongsgaard
Ulf E
UE
Børmer
Ole P
OP
D000418:Albumins / Q000378:metabolism*; D004074:Digitoxin / Q000378:metabolism*; D004345:Drug Industry; D006801:Humans; D009288:Naproxen / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D014859:Warfarin / Q000378:metabolism*
D000418:Albumins; D004364:Pharmaceutical Preparations; D012709:Serum Albumin; D009288:Naproxen; D014859:Warfarin; D004074:Digitoxin