Quantitative structure-activity relationship (QSAR) methodology in forensic toxicology: modeling postmortem redistribution of structurally diverse drugs using multivariate statistics.
Postmortem redistribution (PMR) constitutes a multifaceted process, which renders the analytical results of drug concentrations inaccurate to be interpreted by forensic toxicologists. The aim of the present study was to evaluate whether quantitative structure-activity relationship (QSAR) methodology could serve as an effective tool to estimate the ability of drugs to redistribute across tissue barriers during postmortem period on the basis of their molecular, physicochemical and structural properties. In this aspect, multivariate data analysis (MVDA) was applied to a set of 77 structurally diverse drugs. PMR data expressed by the central:peripheral concentration ratio (C:P ratio) was taken from the literature. An adequate and robust QSAR model (R(2)=0.65, Q(2)=0.56, RMSEE=0.34) was established for 59 (77%) out of 77 drugs. Although the derived QSAR model presented limited applicability, it provided an informative illustration of the contributing molecular, physicochemical and structural properties in PMR process. Drugs with strong basic properties and enhanced molecular size, flexibility, lipophilicity and number of halogens were found to be susceptible to increased PMR. Due to the high complexity of PMR process, further QSAR studies need to focus on structurally related drugs to develop more specific models, which could serve as alternative tools to evaluate PMR for different chemical classes.
Giaginis
Costas
C
Department of Forensic Medicine and Toxicology, Medical School, University of Athens, 75 Mikras Asias Street, Goudi, Athens GR11527, Greece.
Tsantili-Kakoulidou
Anna
A
Theocharis
Stamatios
S