Transportní studie antihistaminik a vliv verapamilu na in vitro model hematoencefalické bariéry

Mandíková, Jana

Studies of drug permeation across the blood-brain barrier (BBB) are an indispensable part of the drug development strategy. Recent in vitro studies have suggested that P-gP and passive membrane permeability may influence the brain concentrations of non-sedating (second generation) H1-antagonists. The purpose of this thesis was to determine the importance of P-gP mediated efflux of the first and the second generation of H1-antagonists in an in vitro BBB model and the influence of P-gP inhibitor verapamil. CNS adverse effects of the first generation of H1-antagonists are linked with their ability to penetrate the BBB and cause sedation and drowsiness. The second and the third generation of H1-antagonists are relatively free of sedation and their limited brain penetration has been suggested to arise from P-gP mediated effux (Obradovic, Dobson et al. 2006). In our in vitro PBMEC/C1-2 model, three H1-antagonists (promethazine, fexofenadine and cetirizine) and a known P-gP substrate rhodamine 123 were tested for their permeation properties. Firstly, P-gP experiments in PBMEC/C1-2 was proven by western blotting. The functional activity of P-gP was assessed by the permeation experiments with an established Transwell in vitro model. The resulting drug quantificantion were evaluated by RP-HPLC and fluorescence...

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