Postmortem metabolomics: Correlating time‐dependent concentration changes of xenobiotic and endogenous compounds

2020 ◽  
Vol 12 (8) ◽  
pp. 1171-1182
Author(s):  
Lana Brockbals ◽  
Sandra N. Staeheli ◽  
Thomas Kraemer ◽  
Andrea E. Steuer
Keyword(s):  
Time Dependent ◽  
Endogenous Compounds ◽  
Concentration Changes

Time- and Site-dependent Postmortem Redistribution of Antidepressants and Neuroleptics in Blood and Alternative Matrices

2020 ◽  
Author(s):  
Lana Brockbals ◽  
Sandra N Staeheli ◽  
Dominic Gascho ◽  
Lars C Ebert ◽  
Thomas Kraemer ◽  
...  
Keyword(s):  
Diffusion Processes ◽  
Individual Variability ◽  
Time Dependent ◽  
Bacterial Degradation ◽  
Thigh Muscle ◽  
Postmortem Changes ◽  
Sample Collection ◽  
Postmortem Redistribution ◽  
Body Regions ◽  
Concentration Changes

Abstract Postmortem redistribution (PMR) leads to challenges in postmortem case interpretation. Particularly antidepressants and neuroleptics are expected to undergo PMR based on their physico-chemical properties. For the current study, time- and site-dependent PMR of 20 antidepressants and neuroleptics were investigated in humans (authentic cases); five of which are discussed in detail (citalopram, mirtazapine, quetiapine, risperidone and venlafaxine) along with two metabolites (9-OH-risperidone and O-desmethylvenlafaxine). Blood [femoral (pB) and heart blood (HB)] and tissue biopsy samples (lung, kidney, liver, spleen, thigh muscle and adipose tissue) were collected upon admission to the institute utilizing a computed tomography-guided sample collection workflow (t1). Approximately 24 h later (t2; mean 23 ± 9.3 h), samples from the same body regions were collected manually. Liquid chromatography–tandem mass spectrometry was used for quantification. Most antidepressants and neuroleptics showed significant time-dependent concentration changes indicating the occurrence of PMR. For the first time, two phases of redistribution in pB for quetiapine were proposed (concentration decreases in the early postmortem phase, followed by concentration increases) and contrasting existing literature, both concentration increases and decreases in pB overtime were observed for risperidone and 9-OH-risperidone. Venlafaxine and its metabolite only showed minimal concentration changes, while citalopram exhibited a trend for concentration increases and mirtazapine for concentration decreases in pB overtime. Based on time-dependent tissue data, passive diffusion processes along the muscle-to-pB, liver-to-HB and lung-to-HB concentration gradients could be proposed along with bacterial degradation. Overall, no case interpretation had to be adjusted, which suggests that PMR changes of antidepressants and neuroleptics do not seem to be relevant for forensic case interpretation within the 24 h period that was investigated. However, limitations of the current study (e.g., temperature-controlled storage of the bodies) could have led to an underestimation of occurring postmortem changes, hence, interpretation of postmortem results should always be conducted with care, considering PMR phenomena and inter-individual variability.

scholarly journals Postmortem Metabolomics: Strategies to Assess Time-Dependent Postmortem Changes of Diazepam, Nordiazepam, Morphine, Codeine, Mirtazapine and Citalopram

Metabolites ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 643
Author(s):  
Lana Brockbals ◽  
Yannick Wartmann ◽  
Dylan Mantinieks ◽  
Linda Glowacki ◽  
Dimitri Gerostamoulos ◽  
...  
Keyword(s):  
Drugs Of Abuse ◽  
Individual Variability ◽  
Time Dependent ◽  
Postmortem Changes ◽  
Knowledge Gain ◽  
Mixed Effect ◽  
Drug Concentrations ◽  
Liquid Chromatography Tandem Mass ◽  
Forensic Case ◽  
Concentration Changes

Postmortem redistribution (PMR) can result in artificial drug concentration changes following death and complicate forensic case interpretation. Currently, no accurate methods for PMR prediction exist. Hence, alternative strategies were developed investigating the time-dependent postmortem behavior of diazepam, nordiazepam, morphine, codeine, mirtazapine and citalopram. For 477 authentic postmortem cases, femoral blood samples were collected at two postmortem time-points. All samples were quantified for drugs of abuse (targeted; liquid chromatography-tandem mass spectrometry LC-MS/MS) and characterized for small endogenous molecules (untargeted; gas chromatography-high resolution MS (GC-HRMS). Trends for significant time-dependent concentration decreases (diazepam (n = 137), nordiazepam (n = 126)), increases (mirtazapine (n = 55), citalopram (n = 50)) or minimal median postmortem changes (morphine (n = 122), codeine (n = 92)) could be observed. Robust mathematical mixed effect models were created for the generalized postmortem behavior of diazepam and nordiazepam, which could be used to back-calculate drug concentrations towards a time-point closer to the estimated time of death (caution: inter-individual variability). Significant correlations between time-dependent concentration changes of morphine, mirtazapine and citalopram with individual endogenous molecules could be determined; no correlation was deemed strong enough for successful a posteriori estimation on the occurrence of PMR for specific cases. The current dataset did successfully lead to a significant knowledge gain in further understanding the time-dependent postmortem behavior of the studied drugs (of abuse).

Postmortem Acetaminophen Pharmacokinetics: An Experimental Study of Site and Time-Dependent Concentration Changes

1995 ◽  
Vol 40 (6) ◽  
pp. 13867J ◽  
Author(s):  
Hernan F. Gomez ◽  
Patrick McKinney ◽  
Scott Phillips ◽  
David V. Roberts ◽  
Jeffrey Brent ◽  
...  
Keyword(s):  
Experimental Study ◽  
Time Dependent ◽  
Concentration Changes

Synaptic transmission : ion concentration changes in the synaptic cleft

1979 ◽  
Vol 206 (1162) ◽  
pp. 115-131 ◽  
Keyword(s):  
Neuromuscular Junction ◽  
Time Course ◽  
Reversal Potential ◽  
Synaptic Cleft ◽  
Time Dependent ◽  
Ion Concentration ◽  
Frog Neuromuscular Junction ◽  
Synaptic Current ◽  
Sodium Depletion ◽  
Concentration Changes

Currents flowing through the postsynaptic membrane of an active synapse will tend to change the concentrations of ions in the synaptic cleft. Published experimental data are used to predict ( a ) the sodium and potassium concentration changes in the cleft at the frog neuromuscular junction, and ( b ) the sodium depletion in the cleft under a Ia synaptic bouton on a cat motoneuron. Significant concentration changes are predicted at both synapses. These changes will contribute to the time dependence of the observed current and will cause the reversal potential of the current to be time dependent. At the frog neuromuscular junction, the time course of the endplate current has been shown previously to depend on the magnitude of the current flowing (at a given potential). We attribute this to changes of the cleft ion concentration. The time dependent changes of the endplate current reversal potential that we predict for the neuromuscular junction are probably too small to be detected. This is because the effects of sodium depletion and potassium accumulation on the reversal potential almost cancel. We predict that near the reversal potential small currents of complex time course will remain, i. e. no true reversal potential exists. Such currents have previously been seen experimentally. At the cat Ia synapse, the synaptic current is predicted to deplete a significant fraction of the available extracellular sodium ions. Consequently, the magnitude of the synaptic current should be relatively independent of the number of postsynaptic channels activated, and of the membrane potential, as has previously been found experimentally.

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