Abstract
Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples. These observations are consistent with meclonazepam having a metabolism similar to that of other nitro containing benzodiazepines such as clonazepam, flunitrazepam, and nitrazepam. Both metabolites were produced by the hepatocytes and in the mice model, but the human liver microsomes were only capable of producing minor amounts of the amino metabolite. However, under nitrogen, the amount of amino-meclonazepam produced increased 140 times. This study comprehensively elucidated meclonazepam metabolism and also illustrates that careful selection of in vitro model systems for drug metabolism is needed, always taking into account the expected metabolism of the tested drug.
Highlights
Meclonazepam, known as (S)-3-methylclonazepam, RO 11-3128, or RO 11-3624, is a benzodiazepine developed and patented by Hoffman-La Roche in 1977 [1] and recently introduced as a drug of abuse [2]
The origin of identified metabolites was verified by collection of urine over 24 h from two mice exposed as well as in human liver microsomes (HLM) and hepatocytes incubated with meclonazepam
We found a signal for a dechlorinated and sulfated amino metabolite in two human urine samples, this compound might originate from synthesis impurities
Summary
Meclonazepam, known as (S)-3-methylclonazepam, RO 11-3128, or RO 11-3624, is a benzodiazepine developed and patented by Hoffman-La Roche in 1977 [1] and recently introduced as a drug of abuse [2]. The pharmacology of meclonazepam has been investigated in clinical trials as an anxiolytic [5] and, interestingly, as a schistosomicidal drug to treat the parasitic worms Schistosoma haematobium and Schistosoma Mansori [6,7]. Meclonazepam can successfully cure parasitic infections with a single dose of at least 0.3 mg/kg, but clinical tolerance was limited by severe adverse drug effects including drowsiness, dizziness, slurred speech, ataxia, muscle weakness, reduced mental alertness, and lateral nystagmus [7]. Boyle et al [8] reported that meclonazepam showed adverse drug effects typical of benzodiazepines, such as clumsiness, feebleness, drowsiness, and mental slowness, with the most pronounced effects within 3 h of oral dosing >1 mg as well as amnesia after a 4-mg dose. Ansseau et al [5] report a potency three times that of
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