Studies on the metabolism of the α‐pyrrolidinophenone designer drug methylenedioxy‐pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC–MS and LC–high‐resolution MS and its detectability in urine by GC–MS

Abstract

Since the late 1990s, many derivatives of the α-pyrrolidinophenone (PPP) drug class appeared on the drugs of abuse market. The latest compound was described in 2009 to be a classic PPP carrying a methylenedioxy moiety remembering the classic entactogens (ecstasy). Besides Germany, 3,4-methylene-dioxypyrovalerone (MDPV) has appeared in many countries in Europe and Asia, indicating its worldwide importance for forensic and clinical toxicology. The aim of the presented work was to identify the phase I and II metabolites of MDPV and the human cytochrome-P450 (CYP) isoenzymes responsible for its main metabolic step(s). Finally, the detectability of MDPV in urine by the authors' systematic toxicological analysis (STA) should be studied. The urine samples were extracted after and without enzymatic cleavage of conjugates. The metabolites were separated and identified after work-up by GC-MS and liquid chromatography (LC)-high-resolution MS (LC-HR-MS). The studies revealed the following phase I main metabolic steps in rat and human: demethylenation followed by methylation, aromatic and side chain hydroxylation and oxidation of the pyrrolidine ring to the corresponding lactam as well as ring opening to the corresponding carboxylic acid. Using LC-HR-MS, most metabolite structures postulated according to GC-MS fragmentation could be confirmed and the phase II metabolites were identified. Finally, the formation of the initial metabolite demethylenyl-MDPV could be confirmed using incubation of human liver microsomes. Using recombinant human CYPs, CYP 2C19, CYP 2D6 and CYP 1A2 were found to catalyze this initial step. Finally, the STA allowed the detection of MDPV metabolites in the human urine samples.

The Toxicology of Bath Salts: A Review of Synthetic Cathinones

“…In another study based on examination of rat urine, MDPV underwent a more complicated metabolism, including oxidative and hydroxylation steps. In this same study, MDPV was found to be metabolized in vitro by CYP isoenzymes 2C19, 2D6, and 1A2 [58].…”

Death Following Recreational Use of Designer Drug “Bath Salts” Containing 3,4-Methylenedioxypyrovalerone (MDPV)

“…Stimulant effects, an increase in libido, anxiety, hallucinations, and paranoid psychosis have been reported [6]. MDPV appears to undergo CYP450 2D6, 2C19, and COMT phase 1 metabolism into methylcatechol and pyrrolidine, which in turn are glucuronidated to allow for renal excretion [11,12]. Although the mechanism of action is not fully elucidated at this time, a dopaminergic mechanism is hypothesized due to the chemical similarity to amphetamines and the behavioral effects of MDPV that mimic those of amphetamines which are known to affect dopaminergic pathways.…”

Psychosis from a Bath Salt Product Containing Flephedrone and MDPV with Serum, Urine, and Product Quantification

“…This likely represents recent exposure to these drugs, as per the patient's history, or could suggest decreased metabolism and excretion of the parent drugs. Studies show that both MDPV and halogenated cathinones undergo extensive hepatic metabolism [16,17]. Genetic heterogeneity in the metabolism of these drugs may play a role in cases of severe intoxications and warrants further investigation.…”