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R. Vadlapatla, D. Kwatra, A. Vadlapudi, A. Mitra; Interaction of Gatifloxacin: A Fourth Generation Fluoroquinolone With Efflux Transporters on Cornea. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1967.
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To screen the interaction of fourth generation fluoroquinolone-Gatifloxacin with efflux transporters like P-gp, MRP and BCRP. The study of interaction of Gatifloxacin with these efflux transporters is necessary to delineate the mechanism of its acquired resistance. The knowledge of this interaction can lead to the development of better strategies to increase bioavailability at target site. This can help in reducing the dose volume further eliminating the chances of systemic toxicity by Gatifloxacin eye drops.
MDCK cell lines transfected with the targeted efflux transporters were used for the study. [14C] Erythromycin was used a model substrate for P-gp and MRP and Hoecht Dye was used as a substrate for BCRP. Uptake and transport studies of these substrates were performed in the presence of Gatifloxacin to determine its interaction with these transporters. Further the efflux ratio of Gatifloxacin by was also calculated using apical to basolateral and basolateral to apical (A-B/B-A) transport studies. Concentration of Hoecht dye was evaluated using fluorescence plate reader
Uptake studies with efflux transporter substrates showed a concentration dependent inhibition effect with Gatifloxacin. The A-B/B-A efflux ratio of efflux transporter substrates was found to reduce to one in presence of increasing concentration of Gatifloxacin. All the studies were verified by using known inhibitors as positive control.
The uptake and transport studies support the hypothesis that Gatifloxacin is a substrate for the efflux transporters. The possible interactions of Gatifloxacin with these efflux trasporters can be the reason for the acquired resistance of Gatifloxacin. This knowledge can be further used to design prodrug or formulation strategies to prevent the acquired resistance and increase the therapeutic efficiency with reduced side effects of the drug.
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