An investigation into the postmortem redistribution of drugs

R Medicine (General)

Kablan, Abbas Mohamed ; Torrance, Hazel

University:University of Glasgow

Department:School of Medicine, Dentistry & Nursing

关键词: Postmortem redistribution of drugs.;   

Others  :  http://theses.gla.ac.uk/74309/7/2019KablanPhD.pdf

来源: University of Glasgow

【 摘 要 】

Postmortem blood drug concentrations change over time as a consequence of postmortem changes and therefore may not reflect the drug concentration at the time of death. In order to reduce the effect of postmortem redistribution on drug concentrations, early collection of samples for analysis is preferable. In addition, many other factors should be considered in the evaluation of drug concentrations in postmortem samples, such as stability of drugs during sample storage as this may be an additional source of variation. The aim of this study was to develop a method for quantifying drug concentrations in postmortem blood samples taken in drug-related deaths. A gas chromatography mass spectrometry (GC-MS) method with solid phase extraction (SPE) was developed and validated for the simultaneous determination of opioids and antidepressant drugs in whole blood. In addition, a liquid chromatography tandem mass spectrometry (LC-MS/MS) method with protein precipitation was developed and validated for simple and accurate analysis of gabapentin, morphine, morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G) in whole blood samples. The methods were successfully verified using authentic postmortem blood samples.This study was designed to understand the stability of morphine and its glucuronides, in real postmortem blood samples, after storage in different conditions for short and long periods of time. The stability study revealed that, the concentrations of free and total morphine were stable during storage in the freezer for ~10 years and no significant losses were observed. The stability study of authentic case samples with and without preservative stored in the freezer for three years revealed that, sodium fluoride and potassium oxalate as a preservative for postmortem blood samples does not affect morphine, M3G and M6G stability under storage temperatures of -20°C for three years.This study also aimed to investigate morphine and morphine metabolites, together with their ratios, in order to achieve a comprehensive interpretation of time since death. The investigation of morphine to the respective glucuronide concentration ratio to estimate the survival times after administration of heroin revealed that, the lower ratios of these conjugates to total morphine (TM), are suggestive of a more rapid death, as there has been less time for the metabolism of morphine to occur. Similarly, the presence of 6MAM in the blood of a heroin toxicity death suggests a more rapid death. More specifically, when M3G/TM is less than 0.40 could show a quick death in the absence of 6MAM in the blood. The purpose of this study was to investigate changes in the concentration of specific drugs (gabapentin, morphine, M3G and M6G) in postmortem blood samples between death and autopsy, and to identify any patterns of these changes. The sampling technique and site of sampling (peripheral and central) were considered to further define the extent of PMR of drugs and identify a possible mechanism of PMR. Concerning sampling site, for all substances, femoral blood concentrations were significantly lower than those found in cardiac blood, indicating that femoral blood is probably less prone to PMR. In addition, the evaluation of drug concentrations in postmortem samples collected using different techniques of blood sampling revealed that, needle puncture in the upper thigh (blind stick) as opposed to dissection of the same vein, also appeared to have an effect on femoral drug concentrations, since femoral concentrations tended to be closer to cardiac concentrations with the dissection sampling than the blind stick sampling technique. Finally, the analytical results derived from sampling (blind stick) as soon as possible to assess whether it is necessary to obtain blood samples prior to autopsy and prevent contamination by PMR, suggest that PMR is a continuous phenomenon in central as well as in peripheral compartments, but also that femoral blood appears more resistant to it.Generally, the results conclude that PMR is an ongoing phenomenon in central as well as in peripheral compartments, but also that femoral blood seems more resistant to it. Therefore, to avoid the effect of the pre-autopsy interval on drug concentrations it is always preferable for early collection of samples for analysis, which are collected closer to the time of death, and would enable a better assessment of the likely contribution of drugs to the death.