Derivatization-free determination of chiral plasma pharmacokinetics of MDMA and its enantiomers.

Two bioanalytical methods—achiral and enantioselective—were developed and validated to measure MDMA and its metabolite MDA in human plasma. Both methods met regulatory guidelines for accuracy, precision, selectivity, and sensitivity over calibration ranges of 0.5–500 ng/mL (achiral) and 0.5–1,000 ng/mL (chiral). The enantioselective method reliably quantified individual enantiomers in racemic samples, and racemic calibrations accurately measured single-enantiomer samples. Pharmacokinetic parameters from clinical participants treated with racemic MDMA or a single enantiomer were comparable between methods. Because MDMA and MDA do not undergo chiral inversion, enantioselective separation is unnecessary when only one enantiomer is administered.

Study at a glance

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is an entactogen with therapeutic potential. The two enantiomers of MDMA differ regarding their pharmacokinetics and pharmacodynamics but the chiral pharmacology of MDMA needs further study in clinical trials. Here, an achiral and an enantioselective high performance liquid chromatography-tandem mass spectrometry method for the quantification of MDMA and its psychoactive phase I metabolite 3,4-methylenedioxyamphetamine (MDA) in human plasma were developed and validated. The analytes were detected by positive electrospray ionization followed by multiple reaction monitoring. The calibration range was 0.5-500 ng/mL for the achiral analysis of both analytes, 0.5-1,000 ng/mL for chiral MDMA analysis, and 1-1,000 ng/mL for chiral MDA analysis. Accuracy, precision, selectivity, and sensitivity of both bioanalytical methods were in accordance with regulatory guidelines. Furthermore, accuracy and precision of the enantioselective method were maintained when racemic calibrations were used to measure quality control samples containing only one of the enantiomers. Likewise, enantiomeric calibrations could be used to reliably quantify enantiomers in racemic samples. The achiral and enantioselective methods were employed to assess pharmacokinetic parameters in clinical study participants treated with racemic MDMA or one of its enantiomers. The pharmacokinetic parameters assessed with both bioanalytical methods were comparable. In conclusion, the enantioselective method is useful for the simultaneous quantification of both enantiomers in subjects treated with racemic MDMA. However, as MDMA and MDA do not undergo chiral inversion, enantioselective separation is not necessary in subjects treated with only one of the enantiomers.