Postmortem Distribution of the Novel Antipsychotic Drug Quetiapine

Abstract

The objective of this research was to determine the concentrations and distribution of the atypical antipsychotic drug, quetiapine, in postmortem tissues from eight Medical Examiner cases. Quetiapine was isolated from liquid specimens and tissue homogenates by extraction at an alkaline pH into 1-chlorobutane. The 1-chlorobutane was decanted, and quetiapine, plus the internal standard (prochlorperazine), was back-extracted into 0.1N sulfuric acid. The acid layer was made basic, and quetiapine, plus the internal standard, was re-extracted into 1-chlorobutane. Quantitation was by gradient, high-pressure liquid chromatography on a C-8 ODS (2.1 x 150 mm, 5 mu) column with acetonitrile/0.1M ammonium hydroxide (pH 10) mobile phase and a photodiode array detector set at 258 nm. The apparent linear range of the assay was from 0.05 to 5.0 microg/mL. At known concentrations of 0.1 and 0.5, interday accuracy (n = 5) was 103.8 and 107.2%, respectively. Interday precision (% cv) at the same concentrations was 9.8 and 9.0, respectively. In the cases where quetiapine was not considered to have contributed to the death, the postmortem concentrations in blood, liver, and bile ranged between 0.15 and 2.7 mg/L (n = 6), 1.3 and 9.5 mg/kg (n = 8), and 10 and 46 mg/L (n = 5), respectively. In the one case involving a quetiapine overdose, concentrations in blood (19.8 mg/L), liver (12.6 mg/kg), and bile (161 mg/L) exceeded the ranges of concentrations determined in specimens from the quetiapine-unrelated deaths.

Late-onset seizures associated with quetiapine poisoning

“…It is rapidly absorbed orally, attains peak plasma concentration in 1-2 hours, is metabolized by liver cytochrome p450 3A4 isoenzyme to the active metabolite 7-hydroxyquetiapine, and is excreted primarily in the urine [1,4,5].…”

“…Hopenwasser et al reviewed 8 medical examiner cases. The article suggests that postmortem therapeutic concentrations that were not related to overdose occur with blood levels between 0.15 and 2.7 mg/L [5]. Drugs with increased lipophilicity, low protein binding, and increased diffusion across gastrointestinal tract into tissues as well as drugs with volumes of distribution >3 L/kg may contribute to increased postmortem redistribution [11].…”

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

“…In this class of compounds, the two leading drugs are clotiapine (129), an anti-psychotic agent, and quetiapine fumarate (130), which is used in the treatment of central nervous system disorders ( Figure 9) [54]. Another compound of interest is F15845 (131); this benzoxathiepine is a blocker of persistent sodium levels and is active in vivo to prevent ischemia and angina [55].…”

A validated GC/MS method for the investigation of quetiapine-related deaths in Greece

“…Serum or plasma concentrations of up to 10 μg/mL have been reported in overdose survivors, whereas post-mortem blood concentrations of up to 25 μg/mL have been reported in fatal cases [17]. It has to be mentioned here that quetiapine may exhibit post-mortem redistribution [20]. In five deaths the heart to femoral blood concentration ratios ranged from 1.4 to 5.4 [21,22].…”