title: Oral bioavailability and intestinal secretion of amitriptyline: Role of P-glycoprotein?
abstract: The aim of the study was to evaluate the influence of quinidine, a P-glycoprotein inhibitor, on oral bioavailability and on intestinal secretion of amitriptyline, a tricyclic antidepressant. Amitriptyline was administrated intravenously (5 mg/kg) and orally (50 mg/kg) to rabbits, with and without quinidine. Jejunal segments of rats were mounted on diffusions chambers and the permeation of amitriptyline was measured across the tissue in luminal-serosal (LS) and serosal-luminal (SL) directions, with and without quinidine. Finally, an in situ recirculating intestinal perfusion model was performed in rabbits to study amitriptyline permeation in LS direction with and without quinidine. Absolute oral bioavailability (F) of amitriptyline was significantly increased more than three-fold in presence of quinidine (F = 0.6+/-0.4% versus 1.9+/-1.1%). The apparent permeability coefficients in SL direction were significantly higher than in LS direction (P(app (SL))=6.01+/-2.42 versus P(app (LS)) = 4.90+/-2.73 x 10(-4) cm min(-1)). In presence of quinidine, the intestinal absorption was increased (P(app (LS)) = 4.02+/-2.91 versus P(app (LS)) = 5.99+/-2.43 x 10(-4) cm min(-1)) and the intestinal secretion was decreased (P(app (SL)) = 4.58+/-0.54 versus P(app (LS)) = 3.63+/-1.46 x 10(-4) cm min(-1)) but not significantly. In conclusion, P-glycoprotein appears to be involved in oral amitriptyline absorption but other intestinal uptake and efflux transporters maybe implicated.
authors.affiliation: Unité UPRES EA 3892, Laboratoire de Pharmacie Galénique, Biopharmacie et Pharmacie Clinique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, 2 avenue du Pr Léon Bernard, 35043 Rennes Cedex, France.
authors.forename: Anne-Yvonne
authors.initials: AY
authors.lastname: Abaut
authors.forename: Francois
authors.initials: F
authors.lastname: Chevanne
authors.forename: Pascal
authors.initials: P
authors.lastname: Le Corre
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000284:Administration, Oral; D000639:Amitriptyline / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology; D007583:Jejunum / Q000378:metabolism; D008297:Male; D011802:Quinidine / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D000639:Amitriptyline; D011802:Quinidine