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Drug Distribution: Tissue Binding01:21

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Upon entering the systemic circulation, drugs can distribute into the interstitial and intracellular fluid of various tissue cells. This distribution is facilitated by the binding of drugs to different cellular components within tissues, which may lead to drug accumulation in specific areas. Drugs bound to tissue components serve as reservoirs that release free drugs back into the system, prolonging the drug's overall action. However, this accumulation can also result in local toxicity.
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Enrichment of Detergent-insoluble Protein Aggregates from Human Postmortem Brain
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Donepezil distribution in postmortem cases and potential for redistribution.

Sayaka Nagasawa1, Suguru Torimitsu2, Fumiko Chiba2

  • 1Department of Legal Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Forensic Science International
|April 25, 2015
PubMed
Summary

Donepezil (DPZ) may redistribute after death, complicating cause of death determination. Postmortem redistribution of DPZ in blood and liver suggests moderate redistribution, influenced by postmortem pH changes.

Keywords:
Central bloodDonepezilLC/MS/MSLiverPeripheral bloodPostmortem redistribution

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Area of Science:

  • Forensic Toxicology
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Donepezil (DPZ) is a primary treatment for Alzheimer's disease.
  • Accurate postmortem drug concentration analysis is crucial for medico-legal investigations.
  • Postmortem redistribution (PMR) can significantly alter drug concentrations, affecting interpretation.

Purpose of the Study:

  • To investigate the potential for postmortem redistribution (PMR) of donepezil (DPZ).
  • To assess factors influencing DPZ concentration, including metabolic variations and organ lesions.
  • To compare DPZ levels in peripheral blood, central blood, and liver tissue postmortem.

Main Methods:

  • Analysis of DPZ concentrations in peripheral blood, central blood, and liver from seven postmortem cases.
  • Calculation of central blood to peripheral blood (C/P) and liver to peripheral blood (L/P) ratios.
  • Examination of factors like metabolic enzyme DNA polymorphism, drug-drug interactions, and organ lesions.

Main Results:

  • DPZ concentrations in peripheral blood, central blood, and liver were often above the therapeutic range.
  • Average C/P ratio was 1.73±1.02, and L/P ratio was 17.5±7.25, suggesting moderate PMR.
  • Lowered postmortem blood pH was observed, potentially increasing ionic DPZ and blood concentrations.

Conclusions:

  • Donepezil (DPZ) exhibits a moderate degree of postmortem redistribution.
  • Postmortem pH reduction may contribute to elevated blood DPZ concentrations.
  • Findings highlight the need to consider PMR in forensic interpretation of DPZ levels.