Evaluation of the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in fed and fasted Greyhound dogs

Abstract

This study reports the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs. Five healthy Greyhound dogs were enrolled in a randomized crossover design. A single oral dose of amitriptyline hydrochloride (actual mean dose 8.1 per kg) was administered to fasted or fed dogs. Blood samples were collected at predetermined times from 0 to 24 h after administration, and plasma drug concentrations were measured by liquid chromatography with mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Two dogs in the fasted group vomited following amitriptyline administration and were excluded from analysis. The range of amitriptyline CMAX for the remaining fasted dogs (n = 3) was 22.8-64.5 ng/mL compared to 30.6-127 ng/mL for the fed dogs (n = 5). The range of the amitriptyline AUCINF for the three fasted dogs was 167-720 h·ng/mL compared to 287-1146 h·ng/mL for fed dogs. The relative bioavailability of amitriptyline in fasted dogs compared to fed dogs was 69-91% (n = 3). The exposure of the active metabolite nortriptyline was correlated to amitriptyline exposure (R(2) = 0.84). Due to pharmacokinetic variability and the small number of dogs completing this study, further studies are needed assessing the impact of feeding on oral amitriptyline pharmacokinetics. Amitriptyline may be more likely to cause vomiting in fasted dogs.

Pharmacokinetics and dynamics of mycophenolate mofetil after single‐dose oral administration in juvenile dachshunds

“…This study was also conducted in a single breed and results may not reflect the juvenile dogs population as a whole. However, single breed pharmacokinetic studies have been used historically and are well represented in the veterinary literature (Kilp, Ramirez, Allan, Roepke, & Nuernberger, ; Norkus, Rankin, & KuKanich, ). Additionally, the possibility that plasma concentrations do not truly reflect tissue concentrations should also be considered.…”

Canine orosomucoid (alpha‐1 acid glycoprotein) variants and their influence on drug plasma protein binding

“…The drugs we chose to study were selected based on previous reports of their high binding affinity for orosomucoid (amitriptyline, lidocaine, and verapamil), and differential binding to orosomucoid variants in humans (indinavir). We investigated plasma drug concentrations below Cmax identified in previous in vivo canine studies (Johnson et al, 1995; Lin et al, 1996; Ngo et al, 1997; Norkus et al, 2015). Equilibrium dialysis was used for determining extent of plasma protein based on previous reports for all analytes (Coyle and Denson, 1984; Curran et al, 2011; Levitt et al, 1986; Sudhakaran et al, 2006).…”

“…Plasma samples were spiked with amitriptyline (120 nM), indinavir (60 nM), verapamil (60 nM), and lidocaine (500 nM) (Johnson et al, 1995; Lin et al, 1996; Ngo et al, 1997; Norkus et al, 2015). Final drug concentrations were chosen based on reported plasma values for dogs and below molar ratio for orosomucoid.…”

Fetal teratogenicity in a rhesus macaque (Macaca mulatta): Association with the chronic maternal treatment of amitriptyline

“…Blood samples from dam, sire, and newborn were collected before, during, and after pregnancy to determine plasma levels of amitriptyline and its active metabolite, nortriptyline 10,11 (Figure 2). Before pregnancy and during gestation, amitriptyline concentrations were higher than nortriptyline concentrations in the dam, as expected for a drug and its metabolite 10,11 . One month before conception (480 days after starting amitriptyline prescription), the sire had detectable levels of both amitriptyline and nortriptyline.…”