The Physicochemical and Pharmacokinetic Properties of Benzodiazepines Appearing as New Psychoactive Substances

Authors: Manchester KR
Publication: University of Huddersfield
Software: ADMET Predictor®


Benzodiazepines are a class of compounds that were initially developed for medicinal purposes. Multiple benzodiazepines have appeared as `new psychoactive substances’ on the illicit drug market and have never been developed for medicinal use. Very little pharmacokinetic data exists regarding them. This information is valuable as it allows the prediction and interpretation of their effects in humans and aids with forensic and toxicological work.

In this work the lipophilicity (log D7.4), the pKa and the plasma protein binding were determined for benzodiazepines appearing as new psychoactive substances and these were compared to theoretical values from software packages. ACD/I-LAB returned the most accurate values for log D7.4 and plasma protein binding while ADMET Predictor returned the most accurate values for pKa. None of the software packages were able to predict parameters to a su_cient degree of accuracy and in vitro data is currently preferable.

An improved relationship to calculate the volume of distribution at steady state (Vdss) by using the Oie-Tozer equation, the log D7.4, the pKa and the plasma protein binding of benzodiazepines was developed. The Vdss of benzodiazepines could be predicted to within a 1.11-fold accuracy.

The blood to plasma concentration ratios of six benzodiazepines appearing as new psychoactive substances were determined. Despite the small dataset a large variation in ratios was observed, from 0.57 for phenazepam to 1.18 for pyrazolam, highlighting the need for accurate pharmacokinetic data.

The metabolic characterisation of illicit compounds is an important aid in toxicological interpretations. This is commonly performed in vitro using human hepatocellular carcinoma cell lines and the choice of cell line is crucial in order to obtain reliable results. The C3A and HepaRG cell lines were characterised with respect to six major phase I metabolic enzymes. HepaRG was shown to have a greater expression of these enzymes and thus have a superior utility in a metabolic study.

The metabolism of 12 benzodiazepines appearing as new psychoactive substances was investigated with the HepaRG cell line. Some of the benzodiazepines were observed to have different metabolic pathways to those previously reported. This again highlights the need for accurate experimental data in order to assess the pharmacokinetics of new psychoactive substances.