Pharmacokinetics of Amitriptyline and One of Its Metabolites, Nortriptyline, in Rats: Little Contribution of Considerable Hepatic First-Pass Effect to Low Bioavailability of Amitriptyline Due to Great Intestinal First-Pass Effect☆

ABSTRACT Pharmacokinetics of amitriptyline and nortriptyline were evaluated after intravenous (2.5–10 mg/kg) and oral (10–100 mg/kg) administration of amitriptyline to rats. The hepatic, gastric, and intestinal first-pass effects of amitriptyline were also measured at a dose of 10 mg/kg. The areas under the plasma concentration–time curve (AUCs) of amitriptyline were dose-proportional following both intravenous and oral administration. After oral administration of amitriptyline, approximately 1.50% of the dose was not absorbed, the extent of absolute oral bioavalability ( F) was approximately 6.30%, and the hepatic and intestinal first-pass effects of amitriptyline were approximately 9% and 87% of the oral dose, respectively. Although the hepatic first-pass effect was 78.9% after absorption into the portal vein, the value was only 9% of the oral dose due to considerable intestinal first-pass effect in rats. The low F of amitriptyline in rats was primarily attributable to considerable intestinal first-pass effect. This study proves the little contribution of considerable hepatic first-pass effect to low F of amitriptyline due to great intestinal first-pass effect in rats. The lower F value of amitriptyline in rats than that in humans (46 ± 48%) was due to grater metabolism of amitriptyline in rats’ liver and/or small intestine