Role of p-glycoprotein in region-specific gastrointestinal absorption of talinolol in rats.
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.
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA. lkagan@buffalo.edu
Leonid
L
Kagan
Tali
T
Dreifinger
Donald E
DE
Mager
Amnon
A
Hoffman
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000818:Animals; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D011412:Propanolamines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D018435:ATP Binding Cassette Transporter, Subfamily B; D011412:Propanolamines; C011550:talinolol