title: Postmortem redistribution of olanzapine following intramuscular administration of olanzapine pamoate in dogs.
abstract: The potential for postmortem redistribution of olanzapine was investigated in beagle dogs. Olanzapine pamoate monohydrate was administered once every 14 days by intramuscular injection for 3 months to fed male dogs (n=15) at a dose of 20 mg/kg olanzapine (equivalent to 46 mg/kg olanzapine pamoate monohydrate). Blood samples were collected after the fifth (Day 57) and sixth (Day 71) doses to determine olanzapine and N-oxide olanzapine concentrations. On Day 71 at 72 h postdose, dogs were euthanized and placed on their backs without additional manipulation and held for postmortem blood, urine, and tissue collection at room temperature for up to 168 h postdose (96 h after euthanasia). Concentrations of olanzapine and N-oxide olanzapine were determined by liquid chromatography-mass spectroscopy/mass spectroscopy (LC-MS/MS). Postmortem olanzapine concentrations in blood increased up to seven-fold compared to the last quantified antemortem blood concentration. Olanzapine concentrations in vein tissue samples (surrogates for peripheral blood) also increased, whereas other tissue concentrations, such as myocardium, lung, liver, and kidney decreased over the postmortem period. An increase in blood concentration of olanzapine after death was observed in all but one animal, suggesting that postmortem redistribution may occur in dogs following biweekly intramuscular administration of olanzapine pamoate monohydrate. The rise in olanzapine concentrations in blood after death in this study may potentially be attributed to diffusion from multiple tissues to blood and, to a lesser extent, reduction of the N-oxide olanzapine metabolite back to olanzapine. However, the generalizability of these results to humans cannot be confirmed by the present study.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: johnson_jason_t@lilly.com.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Johnson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Everly
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Felicia E Frazier
authors.initials: FEF
authors.lastname: Kpakima
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Holland C
authors.initials: HC
authors.lastname: Detke
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004285:Dogs; D007273:Injections, Intramuscular; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D023421:Models, Animal; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D000077152:Olanzapine; D011180:Postmortem Changes
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine
keywords: LC–MS/MS; N-oxide olanzapine; Olanzapine; Postmortem redistribution