Consequently, PMR of drugs may complicate the interpretation of the analytical results in forensic toxicology and has emergently been considered as ‘a toxicological nightmare’ ( 10, 12).
Drugs biotransformation by metabolizing enzymes, such as cytochrome P450 monooxygenases and/or uridine diphosphate-glucuronosyltransferases, could also be triggered at an early stage of postmortem period ( 11). The competing processes of diffusion from drug reservoirs, disruption of cellular membranes and putrefaction may lead to alterations in drug concentrations between sites and sampling intervals ( 9, 10). Redistribution from these organs can occur by diffusion through blood vessels and/or transparietal diffusion toward surrounding organs ( 6– 8). Hollow organs with high concentrating power, such as different parts of the gastrointestinal tract or viscera, liver, lungs and heart, can function as drug reservoirs ( 6– 8). Many drugs are sequestered antemortem in organs qualified as drug reservoirs. The high complexity of PMR process is amplified by the fact that it does not exclusively refer to fatal poisoning, but it may also reflect antemortem physical or biochemical alterations. These site- and time-dependent variations have been attributed to a multifaceted process occurring after death, referred to as postmortem redistribution (PMR) ( 6, 7). This is mainly ascribed to the fact that drug concentrations obtained from postmortem samples do not necessarily reflect the blood concentration at the time of death due to variations according to the sampling site and the interval between death and sampling ( 1– 5).
The interpretation of drug concentrations in postmortem period constitutes one of the most difficult aspects in the field of forensic toxicology. However, the complexity, non-static and time-dependent nature of PMR endpoints raises serious concerns whether QSAR methodology could predict the degree of redistribution, highlighting the need for animal-derived PMR data. Thus, QSAR analysis could be used as a complementary tool to provide an informative illustration of the contributing molecular, physicochemical and structural properties in PMR process. For tricyclic antidepressants, an adequate QSAR model with slightly inferior statistics ( R 2 = 0.95, Q 2 = 0.87, RMSEE = 0.29) was established after exclusion of maprotiline, in which energy parameters, basicity character and lipophilicity exerted significant contribution. For benzodiazepines, an adequate QSAR model was obtained ( R 2 = 0.98, Q 2 = 0.88, RMSEE = 0.12), in which energy, ionization and molecular size exerted significant impact. The present study aimed to apply quantitative structure–activity relationship (QSAR) analysis for modeling PMR data of structurally related drugs, 10 benzodiazepines and 10 tricyclic antidepressants. Postmortem redistribution (PMR) constitutes a multifaceted process, which complicates the interpretation of drug concentrations by forensic toxicologists.
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