A mechanism-based forensic investigation into the postmortem redistribution of morphine

As submitted by the proposer: Postmortem redistribution (PMR) of drugs and their metabolites refers to the changes that occur in drug concentrations after death. One complication in the interpretation of postmortem blood drug concentration is whether the measured drug concentration accurately reflects the concentration at death. Postmortem drug concentrations are also known to show variations depending on sampling site as well as characteristics of the drugs themselves. Similar to antemortem pharmacokinetics, PMR is affected by lipophilicity, degree of ionization (e.g. pka) and volume of distribution. While it was originally thought that the primary source of drug redistribution was diffusion from the cardiac tissues, recent research shows that the redistribution from solid organs such as the lungs, liver, and myocardium is a major contributor. It is important for the field of forensics to continue to research commonly used and/or abused drugs to provide further data into postmortem redistribution and establish significant reference values. These values are particularly valuable in solving the medicolegal issues since medical examiners and coroners use this information to determine a cause and manner of death. Morphine is often found in the postmortem blood samples of patients treated with or abusing the drug, its causation in death has to be considered. Postmortem distribution patterns of morphine have been established in blood, vitreous humor, brain and other samples from human autopsy material however, their relationship to antemortem values has not be extensively studied. The research will address this questions by two testable aims: 1) to evaluate the in vivo postmortem redistribution of morphine in blood and tissues after intravenous administration and 2) to evaluate the influence of alcohol consumption on postmortem redistribution of morphine. Different doses of morphine (5, 10,20 mg/kg) will be administered to adult Sprague-Dawley rats, including both males and females, followed by euthanasia occurring 60 minutes to determine antemortem distribution and postmoretem redistribution of morphine and its metabolites using LC/MS/MS instrumental analysys and pharmacokinetic analysis/modeling. The proposed research will provide an extensive insight into the postmortem redistribution of morphine that can be used throughout the forensic toxicology and pathology field to aide in the interpretation of toxicological results. This project contains a research and/or development component, as defined in the applicable law, and complies with Part 200 Uniform Requirements – 2 CFR 200.210(a)(14). nca/ncf

The redistribution of drugs and their metabolites after death makes it difficult to accurately determine drug concentration at death. Determining concentration at death is vital to establishing whether an individual died as the result of an overdose. The postmortem patterns of morphine have been well characterized. The applicant proposes research that will establish how those patterns related to ante mortem values. "Note: This project contains a research and/or development component, as defined in applicable law," and complies with Part 200 Uniform Requirements - 2 CFR 200.210(a)(14). NCA/NCF