Pharmacokinetic Analysis of Amitriptyline and Its Demethylated Metabolite in Serum and Brain of Rats after Acute and Chronic Oral Administration of Amitrip-tyline.

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

“…6 The experiments on the first-pass effect of amitriptyline in humans are not easy. Thus, rats were used as an animal model in the present studies to measure the first-pass effects of amitriptyline.…”

“…4A). Miyake et al 6 reported that amitriptyline is demethylated in rat liver to its primary active metabolite, nortriptyline. However, the AUC values of nortriptyline after both intragastric and intraduodenal administration of amitriptyline were significantly smaller than that after intraportal administration of amitriptyline (Tab.…”

“…The great intestinal first-pass effect of amitriptyline for the reason of the low F, although the hepatic first-pass effect is considerable, is also reported. The possible reasons for the lower F value in rats 6 than that in humans 1,2 were again reported.…”

“…Although the values were not measured, existence of the first-pass effect of amitriptyline has been reported in humans. [3][4][5] Miyake et al 6 reported that after single oral administration of amitriptyline at a dose of 20 mg/kg to male Sprague-Dawley rats, the F of the drug is 4.4%. Breyer-Pfaff et al 7 reported that in rats, amitriptyline is metabolized to 18 metabolites including nortriptyline, and nortriptyline is further metabolized to 8 metabolites in the 9-h bile samples.…”

“…Breyer-Pfaff et al 7 also reported hydroxylation metabolites of amitriptyline in rats. 7 Studies on the pharmacokinetics of amitriptyline in humans 2,3-5, 8 and rats 6,[9][10][11] have been published, however, no studies on the reasons for the incomplete (low) F values have yet been published. Thus, in the present study, the reasons for the incomplete (low) F values of amitriptyline were evaluated using rats as an animal model.…”