Experimental estimation of the role of P-Glycoprotein in the pharmacokinetic behaviour of telithromycin, a novel ketolide, in comparison with roxithromycin and other macrolides using the Caco-2 cell model.

PURPOSE: The aim of this study was to examine the transport mechanism of telithromycin in comparison with erythromycin, azithromycin, clarithromycin and roxithromycin. METHODS: These antibiotics were examined in Caco-2 cell monolayers in order to demonstrate the potential involvement of P-GP in the absorption process, using verapamil as a P-GP competitor. A model using concentration equilibrium conditions was developed to delineate passive and active permeability components of telithromycin and roxithromycin transport in order to predict absorption in humans. RESULTS: Comparison of telithromycin Papp(AB)/Papp(BA) ratios with those of the other antibiotics indicated that an efflux pump was involved which limited the transport of the macrolides to a greater extent than that of telithromycin. Modulation of Caco-2 transport of these antibiotics by verapamil and their reciprocal effect upon verapamil transport confirmed the involvement of P-GP and demonstrated that two substrates of P-GP may increase the transport of each other. Under concentration equilibrium conditions, both roxithromycin and telithromycin exhibited high mean Papp values for passive diffusion which extrapolated to 88% and 77% predicted human absorption respectively, if the involvement of P-GP was ignored. Both Km and Vm values suggested that saturation of P-GP by telithromycin may occur at a lower dose level in humans than with roxithromycin (Km= 9.8 microM, Vm= 0.3 microM and Km= 45 microM, Vm= 1.1 microM, respectively). At 4.10(-5) M of either telithromycin or roxithromycin the passive flux was respectively 48% and 16% greater than the active efflux. CONCLUSIONS: The high absorption potential of telithromycin combined with the low Km and Vm values and the high dose level suggest that in humans the efflux pump may not limit ketolide absorption and that the interaction with other P-GP substrates may not significantly increase its oral absorption.