Postmortem serum and tissue redistribution of fluoxetine and norfluoxetine in dogs following oral administration of fluoxetine hydrochloride (Prozac).
Antemortem serum and postmortem serum and tissues were evaluated to determine if postmortem redistribution of the antidepressant, fluoxetine (Prozac) and its major active metabolite, norfluoxetine, occurred in dogs following oral administration of fluoxetine hydrochloride. Beagle dogs (four males) received daily oral doses of 10 mg fluoxetine/kg for five days. Antemortem serum concentrations of fluoxetine and norfluoxetine were determined 3 and 24 h following administration of the first four daily doses of fluoxetine and 3 h after the fifth dose in order to monitor for steady-state serum concentrations of parent and metabolite prior to postmortem serum concentration determinations. Antemortem serum concentrations of fluoxetine and norfluoxetine 3 h postdose on Day 5 ranged from 530 to 1210 ng/mL and 1460 to 1980 ng/ mL, respectively. Immediately following the 3 h blood sample on Day 5, each dog was euthanized. Serum concentrations of fluoxetine and norfluoxetine were determined from blood samples collected from the vena cava, heart, and clotted blood within the heart at 2 h after death in two dogs and 12 h after death in the remaining two dogs. Similarly, tissue concentrations of fluoxetine and norfluoxetine in heart, liver, and lung were determined 2 and 12 h postmortem. Serum concentrations of fluoxetine and norfluoxetine from the vena cava and heart 2 h postmortem were 2.2- to 6.0-fold and 2.3- to 3.6-fold higher, respectively, than antemortem serum concentrations. Similarly, serum concentrations of fluoxetine and norfluoxetine from vena cava and heart 12 h postmortem were 1.3- to 3.5-fold and 1.7- to 3.3-fold higher, respectively, than antemortem serum concentrations. However, 2-h and 12-h postmortem serum concentrations of fluoxetine and norfluoxetine from clotted blood within the heart were equal to or less than levels determined in antemortem serum. Results from 2-h and 12-h postmortem average tissue concentrations of fluoxetine and norfluoxetine in heart, liver, and lung demonstrated that fluoxetine and norfluoxetine concentrations in myocardium were similar 2 h and 12 h postmortem. However, in liver, fluoxetine concentrations decreased 39% and norfluoxetine concentrations decreased 23% from 2 h to 12 h postmortem. Even greater postmortem decreases in fluoxetine and norfluoxetine concentrations were observed in lung. Fluoxetine and norfluoxetine concentrations in lung decreased 49% and 39%, respectively, from 2 h to 12 h postmortem. In conclusion, this study demonstrated that fluoxetine and norfluoxetine undergo postmortem redistribution in the dog. Furthermore, postmortem serum concentrations appear to be dependent on the sample site and the degree of coagulation of the blood. Finally, postmortem decreases in concentrations of fluoxetine and norfluoxetine in liver and lung may, in part, explain the observed increase in serum concentrations at 2 and 12 h postmortem.
Pohland
R C
RC
Toxicology Research Laboratories, Lilly Research Laboratories, A Division of Eli Lilly and Company, Green-field, IN, USA.
Bernhard
N R
NR
D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D005473:Fluoxetine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008099:Liver / Q000737:chemistry; D008168:Lung / Q000737:chemistry; D008297:Male; D009206:Myocardium / Q000737:chemistry; D011180:Postmortem Changes; D014018:Tissue Distribution
D005473:Fluoxetine; C036139:norfluoxetine