Abstract
The binding of carbenoxolone to crystalline bovine and human albumin was measured in vitro by equilibrium dialysis, ultrafiltration and fluorescent probe techniques. Comparison of the results of these methods did not provide a good correlation, although it was clear that marked species differences in binding were evident with each method. Carbenoxolone and phenylbutazone share a single class binding site on bovine albumin, but are bound at different sites on human albumin. A fluorescent probe technique was chosen to compare the binding of carbenoxolone with that of other drugs. The binding of the probe, 1-anilino-8-naphthaIene sulphonic acid, to human albumin revealed two distinct binding sites on human albumin, which enabled the drugs to be classified into three groups. Two of the groups bind at only one site whilst the third group was bound at both sites. Carbenoxolone was the most strongly bound member of its group which included: cicloxolone, indomethacin, enoxolone and cholesterol. The second group of drugs comprised: flufenamic acid, phenylbutazone, warfarin, tolbutamide and imipramine. The remaining drugs, bound at both sites, consisted of prednisolone, aspirin, ibuprofen, chlorpropamide and phenytoin. It was inferred that carbenoxolone would displace the other members of its group, would not displace the drugs in group 2, and may displace the drugs in group 3 from their common binding sites. Models of interaction in vivo were established using the rat, whereby phenylbutazone was shown to potentiate the pharmacological activity of warfarin, tolbutamide and chlorpropamide. In the same models carbenoxolone was without effect on these drugs. Neither phenylbutazone nor carbenoxolone affected the activity of phenytoin in the rat, probably due to the relatively low protein binding of phenytoin in the rat. Further studies in the rat demonstrated a decrease in the plasma half-life of warfarin and an increase in the whole blood half-life of tolbutamide when phenylbutazone was co-administered. Carbenoxolone did not alter the pharmacokinetics of these two drugs. Serum concentrations of carbenoxolone in both rat and man were unaltered by the concomitant administration of warfarin, tolbutamide, chlorpropamide or phenytoin. In conclusion, carbenoxolone was shown to be free from many of the displacement interactions demonstrated with other drugs which are bound to plasma proteins.