Oral bioavailability and intestinal secretion of amitriptyline: Role of P-glycoprotein?

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 (Papp (SL) = 6.01 ± 2.42 versus Papp (LS) = 4.90 ± 2.73 × 10−4 cm min−1). In presence of quinidine, the intestinal absorption was increased (Papp (LS) = 4.02 ± 2.91 versus Papp (LS) = 5.99 ± 2.43 × 10−4 cm min−1) and the intestinal secretion was decreased (Papp (SL) = 4.58 ± 0.54 versus Papp (LS) = 3.63 ± 1.46 × 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.