Abstract

P-Glycoprotein (PGP) is nonuniformly distributed along the gastrointestinal (GI) tract; however, the data regarding regional differences in PGP function in the intestine are controversial. The aim of this work was to investigate the role of PGP efflux in region-specific absorption of talinolol from the GI tract in rats. Plasma talinolol concentrations were measured after several modes of administration, including high (40 mg/kg) and low (4 mg/kg) dose levels, to different segments of the GI tract (stomach versus colon), and codosing with PGP inhibitors (verapamil or cyclosporine). The bioavailability (F) of talinolol after high-dose administration to the stomach was significantly greater than that achieved by the low dose (approximately 18 versus 2%). Coadministration of low-dose talinolol with cyclosporine increased F by approximately 5-fold (p < 0.01). For the high dose, codosing with PGP inhibitors did not increase the extent of absorption. Talinolol demonstrated poor colonic absorption that was significantly increased by coadministration with cyclosporine (F = 0.76 versus 8.1%). Oral verapamil significantly increased systemic clearance and the steady state volume of distribution of intravenous talinolol. A semiphysiological model was developed that successfully captured the pharmacokinetic profiles of talinolol after various modes of administration. PGP-mediated efflux appears to be a major factor responsible for GI region-specific absorption of talinolol in rats, and gastroretentive dosage forms may provide an advantage in the delivery of talinolol and PGP substrate drugs.