IN-VITRO STUDY OF THE PROTEIN-BINDING OF FUSIDIC ACID - A CONTRIBUTION TO THE COMPREHENSION OF ITS PHARMACOKINETIC BEHAVIOR

Fusidic acid (FA: Fucidine(R) Leo Laboratories) is a type I drug: acid , ionized at plasma pH, with a high intrinsic affinity for albumin. In the case of this kind of product, the possibility exists of the satur ation of protein binding and of drug interactions. The relative affini ty of fusidate (F) for different solutions of albumin was compared in vitro, i.e., purified industrial albumin, fresh frozen plasma, and pla sma from surgical intensive care unit (ICU) patients. The theoretical consequences of the albumin status of a patient on FA kinetics were en visaged in the form of a model. The three stock solutions were diluted such that solution S1 yielded concentrations of 38, 29 and 19 g/l of albumin, and S2 provided concentrations of 44, 32 and 20 g/l of albumi n. The concentration of solution S3 was initially 24 g/l (severe hypoa lbuminemia). The seven solutions were spiked with known quantities of FA (10, 50, 100 and 150 mg/l) in which total F (tF) and free F (fuF) w ere assayed by HPLC. The per cent binding of F to albumin was determin ed, as was the number of binding sites (n) and its saturable or non-sa turable character as a function of the medium (Scatchard plots). The c onclusions drawn were: (1) the number of F binding sites on albumin is between two and three and the per cent binding of F is in the range o f 91.5-98.7%; (2) Fucidine(R) belongs to the group of drugs sensitive to the albumin status of the media in which it is added; (3) the often severe hypoalbuminemia of ICU patients may lead to a considerable inc rease in the active fraction fuF; the most seriously affected patients should be more exposed to variations in the tF/fuF ratio; (4) the cli nical status of the patients (kidney failure, malnutrition hypoalbumin emia, etc.) should be taken into account when determining the dosage s chedules of parenterally administered FA, In summary, after repeated a dministration, the significant increase in fuF should induce the follo wing: an increase in V-d, an increase then a decrease in Cl, a decreas e then an increase in the AUC. The hypothesis according to which Fucid ine(R) would be more effective in the hypoalbuminemic patient remains to be confirmed in selected patients with coupled measurements of tF a nf fuF.