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.
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.
Bae
Soo K
SK
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Yang
Kyung H
KH
Aryal
Dipendra K
DK
Kim
Yoon G
YG
Lee
Myung G
MG
D000284:Administration, Oral; D000639:Amitriptyline / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000378:metabolism; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009661:Nortriptyline / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000639:Amitriptyline; D009661:Nortriptyline