Tissue distribution and metabolism of amitriptyline after repeated administration in rats

Plasma concentration, tissue distribution, and metabolism of amitriptyline (AMI) in rats pretreated with AMI (20 mg/kg/day, ip dose, for 7 days; treated) were compared with control rats. Plasma concentrations of AMI after intravenous administration (2 and 10 mg/kg) to the treated rat were significantly higher than those to the control rat in both doses. The difference in the plasma concentration between both groups may be caused by a change of tissue distribution of AMI, because the blood cell-to-plasma concentration ratio and the tissue-to-blood concentration ratio values for various tissues in the treated rat were smaller than those in the control, respectively. The plasma unbound fraction of AMI in the treated rat was significantly smaller (p < 0.05). alpha 1-Acid glycoprotein concentration in plasma of the treated rat was approximately twice that in the control rat. These results suggest that the decrease of tissue distribution of AMI in the treated rat may be caused by the decrease in the plasma unbound fraction of AMI with the increase of alpha 1-acid glycoprotein in plasma. The area under the plasma concentration-time curve for AMI and its main metabolite, nortriptyline, in the treated rat after intraportal administration of AMI was 1/3 and 3-fold those in the control rats, respectively. On the other hand, the hepatic intrinsic clearance (CLH,Int) of the unbound drug in the treated rat was approximately twice that of the control, suggesting that the increase of the (CLH,Int) by repeated administration of AMI may result in the induction of oxidative metabolism.