Permeation in artificial membrane of allopurinol derivatives with potentila anti- T.cruzi activity

GUALDESI M., LONGHI M., GRANERO G., RAVIOLO M.

Córdoba

Congreso; 3º Reunión Internacional de Ciencias Farmacéuticas. RICifa 2014; 2014

Introduction: Chagas disease is caused by Trypanosoma cruzi (T. cruzi), and is a major health problem in Central and South America that affects nearly 8-10 million people. Allopurinol (Allop) is a hypoxantine analog used by the T. cruzi as an alternative purine substrate. Although Allop presents trypanocidal activity, its failure avoiding Chagas progression may be due in part to inadequate blood levels caused by unfavorable physicochemical properties, thus leading to versatile responses in humans. In an attempt to improve its performance, we have developed twelve derivatives of Allop by chemical modification, resulting in active anti-T cruzi agents per se or prodrugs compounds.1 The present study deals with the permeability of Allop and its derivatives by using artificial membranes as an in vitro technique that represent an interesting alternative to the use of animal tissues or cells because of its simplicity, addition to showing comparable results to Caco-2 permeability. Methods: The passive diffusion was evaluated using Franz diffusion cells with an artificial membrane constructed by lipids and n-octanol on a hydrophilic membrane support and cells pH 5.5donor ? pH 7.4acceptor at 37 °C.2 To obtain each apparent permeability coefficient, each experiment was performed in triplicate and 14 samples were taken over a period of 4 h and quantified by Micellar Liquid Chromatography. Results: All Allop derivatives increased the percentage of absorbed fraction with respect to Allop (77.1 to 99.9% and 65.9%, respectively), which provides an important pharmacokinetic advantage. Those compounds having a Log Po/w> 1% have a fraction absorbed > 90%, while for the those compounds having a Log Po/w ≤ 1, there are different physicochemical properties that play an important role in the percentage permeation such as polar surface area, molecular rigidity, H-bond donor and H-bond acceptor. It proved suitable the use of the in vitro technique for the determination of the permeability of Allop derivatives.