Biopharmaceutic evaluation of some 4-quinolone derivatives

The relationships between physicochemical properties (ionization, solubility, partition, protein binding) of 4-quinolone derivatives and their pharmacokinetics was studied by means of in vitro methods. This information is needed to clarify the erratic absorption behaviour of quinolone antibacterials following oral administration. The ionization constants of ofloxacin (OF), pefloxacin (PF), norfloxacin (NF) and ciprofloxacin (CF) were determined by solubility, potentiometric, spectrophotometric, and octanol-water partition methods. The quinolones are ampholytes showing small values of partition coefficients (order of magnitude 1) resulting from their hydrophilic nature. Within the series, both partition coefficients and the ionization constants differ only slightly (5.5 less than pK1 less than 6.5, and 7.5 less than pK2 less than 8.5). The intrinsic solubility of nonionized forms of drugs was obtained to be of 1g/l order of magnitude. Linear relationship was observed between the log solubility versus reciprocal temperature. The dissolution of NF is an endothermic reaction with dissolution enthalpy H = 20.4 kJ/mol. In vitro diffusion of OF, PF, NF, and CF was studied by the means of Sartorius in vitro absorption model. The rate of diffusion and the projected in vitro rate of absorption are not functions of structural differences within the series (diffusion rate constant range was 0.5 less than kd less than 5.0 .10-3 cm/min). Binding of NF, CF, PF and OF to bovine serum albumin (BSA) was studied using equilibrium dialysis in the absence and presence of urea. It was found that the quinolones were moderately bound (40-60%) to BSA and that urea in pathologic concentrations diminished their binding for 10-25%.