Correlation of bile and vitreous humor concentrations with blood drug concentrations for forensic interpretation: a comparative study between animal experimental and human postmortem data

摘要

Forensic toxicology involves two possible levels of interpretation: qualitative (detection of xenobiotic consumption by the victim) and quantitative (assessing the implication of xenobiotics in death). Based on six drugs (meprobamate, morphine, cyamemazine, caffeine, diazepam, and citalopram) used as test substances, an animal experiment was combined with a series of autopsy cases to assess both qualitatively and quantitatively the use of bile and vitreous humor (VH) as alternative matrices to blood. The six molecules were administered to rabbits at various time points prior to euthanasia, and a human autopsy series (n > 20) was set up for each molecule. Bile, blood, and VH were analyzed using gas chromatography-tandem mass spectrometry (GC-MS/MS) according to two previously published methods. Ratios and correlations between bile/blood and VH/blood concentrations were determined. Both bile and VH demonstrated value qualitatively, allowing detection of all six molecules, possibly with longer detection windows than with blood. All six molecules showed a significant correlation between blood and VH concentrations in rabbits, whereas no such correlation was found in the autopsy series for cyamemazine or diazepam. In bile, correlations were found for meprobamate and caffeine in both rabbits and humans. Thus, bile and VH can be interpreted quantitatively for certain molecules. Combining the two experimental approaches demonstrated the impact of forensic (drug intake-to-death interval) and other parameters such as unbound fraction and molecular mass on xenobiotic distribution in these two alternative matrices. Pharmacokinetic and physicochemical parameters influencing the distribution of molecules were thus proposed, and were recommended to be taken into account when interpreting the behavior of other drugs.