ABSTRACT:The binding of 17 drugs to rat hepatocytes has been determined using equilibrium dialysis in combination with metabolic inhibitors and a kinetic model for the binding and dialysis processes. Metabolic inhibitors were used to retard the main routes of metabolism such that the half-life for turnover of the drugs was comparable to or greater than the time scale of the equilibrium dialysis process. Further experiments were carried out to determine the kinetics of diffusion of the compounds across the dialysis membrane and the observed extent of binding to hepatocytes. Knowledge of the rate of metabolism of the drugs in the presence of the inhibitors, the kinetics of the dialysis process, and the observed extent of binding was then used with a kinetic model of the system to give true free fractions of the drugs in live hepatocytes. Further studies show that, for this set of compounds, there is no significant difference in the extent of binding to live or dead hepatocytes. The extent of hepatocyte binding is correlated with lipophilicity, and the best model for binding uses log P for basic compounds and log D 7.4 for acidic and neutral compounds. Hepatocyte binding is also demonstrated to be highly correlated with microsome binding.The kinetic data from microsome or hepatocyte intrinsic clearance assays are often used for the prediction of in vivo metabolic clearance through the use of in vitro-in vivo scaling using methods such as the well stirred model and the parallel tube model (Pang and Rowland, 1977). It has been recognized that nonspecific binding in the in vitro metabolic assay medium can significantly affect the observed kinetics of metabolism and hamper the accurate prediction of clearance. Nonspecific binding has been fairly well studied using microsomes, and there are several examples where knowledge of the extent of microsomal binding leads to a better understanding of the relationship between in vitro metabolism and in vivo pharmacokinetics (Lin et al.,

Redx Pharma has discovered a novel series of topoisomerase inhibitors that are being further developed for drug-resistant bacteria.

There is an urgent need for new antibiotics to treat multidrug-resistant Neisseria gonorrhoeae. In this report, the microbiology, in vivo pharmacokinetics, and efficacy of REDX05931, a representative novel tricyclic topoisomerase inhibitor, were evaluated. REDX05931 demonstrated high oral bioavailability in mice and reduced N. gonorrhoeae infection after a single dose in a mouse model of gonorrhea. These data support the potential of this series of small molecules as a new treatment for drug-resistant gonorrheal infections.

The discovery of novel tricyclic topoisomerase inhibitors (NTTI's) that address fluoroquinolone resistance.

We disclose the discovery of REDX07965, a novel tricyclic topoisomerase inhibitor (NTTI) which has broad spectrum activity, favourable in vitro pharmacokinetic properties and selectivity versus human topoisomerase II.