P-GLYCOPROTEIN TRANSPORTERS AND THE GASTROINTESTINAL-TRACT - EVALUATION OF THE POTENTIAL IN-VIVO RELEVANCE OF IN-VITRO DATA EMPLOYING TALINOLOL AS MODEL-COMPOUND

Among the different application routes peroral administration remains the one most widely used, Hence, mechanisms affecting p.o. bioavailabi lity are of particular interest, also in drug development, In recent y ears, intestinal drug Secretion mediated by the multi-drug resistance gene product P-glycoprotein (PEP) has been discovered as a possible me chanism of low and erratic bioavailability, Due to the saturability of this process, a dose-dependent apparent oral clearance may be observe d which decreases upon increasing dose, However, in vivo intestinal se cretion might be revealed only in the lower or subtherapeutic dose ran ge, in permeability studies with Caco-2 cell monolayers, the MDR-rever sing agent verapamil inhibits secretion of P-glycoprotein substrates a nd, hence, increases apical-to-basolateral permeability. The aim of th e rat studies with talinolol presented here was to test the relevance of the intestinal secretion process as well as the extent of inhibitio n by verapamil in ex vivo, in situ, and in vivo talinolol/verapamil dr ug-drug interaction studies. Intestinal secretion of talinolol was det ected indirectly in ex vivo studies via transport inhibition with vera pamil and directly in in situ intestinal perfusions in rats following a talinolol i.v. bolus. Both i.v, and p.o. verapamil appear to affect the concentration-time profiles of talinolol. Relevant observations wi th respect to drug absorption are the decreased apparent oral clearanc e upon verapamil coadministration as well as the decreased t(max) and mean absorption times at high verapamil doses. Talinolol may be regard ed as a potential model compound for mechanistic studies on Pgp intera ctions, including permeability as well as binding studies and the invo lvement of transporters other than Pgp.