Spectroscopic Studies as a Biophysical Toolbox for Pharmacokinetic Drug Profiling

Abstract

The rationalization of the drug development process is a requirement both in pharmaceutical industries, and in academic research laboratories. Given the urge to improve the drug discovery process, in vitro screening assays are developed to measure the so called drug property profile which can be useful to medicinal chemists in deciding how to modify structures to improve properties of their drug candidates decreasing development time/cost and delay clinical introduction. Herein it is presented the study of the biophysical interactions of newly synthesized drugs with membrane model systems, using some systematic spectroscopic techniques to establish a pharmacokinetic drug profiling.Liposomes mimicking different body membrane barriers were prepared and further labelled with suitable membrane probes. The interactions of drugs with lipid membranes were used to determine their membrane/water partition coefficient, which is a predictor of drug affinity to the membranes as well as drug permeability and absorption. Further information about the degree of penetration of the drugs in the lipid membranes was also gained through in depth-dependent fluorescence quenching experiments (steady-state and time-resolved). In addition, it was possible to monitor the fluidity gradient through a bilayer leaflet by measurements of temperature dependent fluorescence anisotropy to evaluate the influence of the drugs changing the cooperativity and the main phase transition temperature which are important to predict toxic effects of drugs at the membrane level.Results obtained provide an insight at the use of spectroscopic techniques as a toolkit for in vitro screening of drug-membrane biophysical interactions to predict with confidence in vivo aspects related with drug absorption and distribution.AcknowledgementsM.Lucio acknowledges FCT for the exploratory project with the reference IF/00498/2012.