Biophysical Models as an Approach To Study Passive Absorption in Drug Development: 6-Fluoroquinolones

A preliminar study attempting to assess and explain the intestinal absorption of a series of antibacterial 7‐piperazinyl‐6‐fluoroquinolones is presented. The synthesis,n‐octanol partition coefficients, intrinsic rat gutin situabsorption rate constants, andin vitroantibacterial activity data found for these homologous compounds are described. A fluorimetric, reverse‐phase HPLC method was performed for the quantification of the quinolones in absorption and partition samples. Equations based on two classic biophysical absorption models are given for predicting the intrinsic absorption features of the series according to the partition data or merely single structural parameters.In situabsorption rate constants were found to increase by a factor of 9.7–13.5 for moderately lipophilic derivatives relative to the simplest compound, while antibacterial activity decreased only by a factor of 4.In vivoabsorption tests with two representative members of the series were carried out and the results showed a good accordance with those foundin situ.This makes these compounds or related ones with similar partition features excellent candidates for further pharmacokinetic and pharmacological testing. The study can serve as an example of how to prevent potential absorption problems associated with the development of new drugs.