In vitro study of the protein binding of fusidic acid: A contribution to the comprehension of its pharmacokinetic behaviour

Fusidic acid (FA: Fucidine® 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 saturation of protein binding and of drug interactions. The relative affinity of fusidate (F) for different solutions of albumin was compared in vitro, i.e., purified industrial albumin, fresh frozen plasma, and plasma from surgical intensive care unit (ICU) patients. The theoretical consequences of the albumin status of a patient on FA kinetics were envisaged 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 albumin. The concentration of solution S3 was initially 24 g/l (severe hypoalbuminemia). 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) were assayed by HPLC. The per cent binding of F to albumin was determined, as was the number of binding sites (n) and its saturable or non-saturable character as a function of the medium (Scatchard plots). The conclusions 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 of 91.5-98.7%; (2) Fucidine® 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 increase in the active fraction fuF; the most seriously affected patients should be more exposed to variations in the tF/fuF ratio; (4) the clinical status of the patients (kidney failure, malnutrition hypoalbuminemia, etc.) should be taken into account when determining the dosage schedules of parenterally administered FA. In summary, after repeated administration, the significant increase in fuF should induce the following: an increase in Vd, an increase then a decrease in Cl, a decrease then an increase in the AUC. The hypothesis according to which Fucidine® would be more effective in the hypoalbuminemic patient remains to be confirmed in selected patients with coupled measurements of tF anf fuF.