Pohland R C, Bernhard N R
Toxicology Research Laboratories, Lilly Research Laboratories, A Division of Eli Lilly and Company, Green-field, IN, USA.
J Forensic Sci. 1997 Sep;42(5):812-6.
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.
对生前血清、死后血清及组织进行评估，以确定口服盐酸氟西汀后，犬体内抗抑郁药氟西汀（百忧解）及其主要活性代谢物去甲氟西汀是否会发生死后再分布。比格犬（4只雄性）连续5天每日口服10mg氟西汀/千克。在给予前四个每日剂量的氟西汀后3小时和24小时以及第五个剂量后3小时测定氟西汀和去甲氟西汀的生前血清浓度，以便在测定死后血清浓度之前监测母体和代谢物的稳态血清浓度。第5天给药后3小时，氟西汀和去甲氟西汀的生前血清浓度分别为530至1210ng/mL和1460至1980ng/mL。在第5天采集3小时血样后，立即对每只犬实施安乐死。在两只犬死亡后2小时和另外两只犬死亡后12小时，从腔静脉、心脏及心脏内的凝血中采集血样，测定氟西汀和去甲氟西汀的血清浓度。同样，在死后2小时和12小时测定心脏、肝脏和肺中氟西汀和去甲氟西汀的组织浓度。死后2小时，腔静脉和心脏中氟西汀和去甲氟西汀的血清浓度分别比生前血清浓度高2.2至6.0倍和2.3至3.6倍。同样，死后12小时，腔静脉和心脏中氟西汀和去甲氟西汀的血清浓度分别比生前血清浓度高1.3至3.5倍和1.7至3.3倍。然而，心脏内凝血中氟西汀和去甲氟西汀的死后2小时和12小时血清浓度等于或低于生前血清中测定的水平。死后2小时和12小时心脏、肝脏和肺中氟西汀和去甲氟西汀的平均组织浓度结果表明，心肌中氟西汀和去甲氟西汀的浓度在死后2小时和12小时相似。然而，在肝脏中，从死后2小时到12小时，氟西汀浓度下降了39%，去甲氟西汀浓度下降了23%。在肺中观察到氟西汀和去甲氟西汀浓度在死后下降得更多。从死后2小时到12小时肺中氟西汀和去甲氟西汀浓度分别下降了49%和39%。总之，本研究表明氟西汀和去甲氟西汀在犬体内会发生死后再分布。此外，死后血清浓度似乎取决于采样部位和血液的凝固程度。最后，肝脏和肺中氟西汀和去甲氟西汀浓度在死后的下降可能部分解释了在死后2小时和12小时观察到的血清浓度升高现象。
