Plasma determination of 3-methylclonazepam by capillary gas chromatography

Coassolo, Philippe; Aubert, Claude; Cano, J. P.

doi:10.1016/0378-4347(85)80105-5

Cited by 17 publications

(9 citation statements)

References 4 publications

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“…While no studies of meclonazepam stability in urine are known to us, Zaitsu et al (24) reported that aminoflunitrazepam was degraded both by bacteria during storage at 4°C and by adhesion to vessel surface. On a similar note, Coassolo et al (12) reported that meclonazepam at 1 ng/mL in plasma was stable at −20°C for 3 months in polypropylene tubes but not in glass tubes nor at room temperature for 24 h.…”

Section: Discussionmentioning

confidence: 80%

“…Based on data from a single patient published by Coassolo et al (12), the bioavailability can be estimated to be close to 100%, volume of distribution to be around 300 L and a plasma half-life approximately 80 h. Ansseau et al (5) report meclonazepam half-life to be 40 h. Coassolo et al (12) claim amino-meclonazepam, 3-methylhydroxy-meclonazepam, and amino-3-methylhydroxy-meclonazepam to be metabolites but provide no data (12). This is in agreement with Huppertz et al (2) who described two metabolites generated in human liver microsome experiments, amino-meclonazepam, and a hydroxylated metabolite.…”

Section: Introductionmentioning

confidence: 99%

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Identifying Metabolites of Meclonazepam by High-Resolution Mass Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and Authentic Urine Samples

Vikingsson

Wohlfarth

Andersson

et al. 2017

AAPS J

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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 highresolution 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 aminomeclonazepam 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.KEY WORDS: benzodiazepine; in vitro metabolism; LC-MS/MS; new psychoactive substance; toxicokinetics.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Identifying Metabolites of Meclonazepam by High-Resolution Mass Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and Authentic Urine Samples

Vikingsson

Wohlfarth

Andersson

et al. 2017

AAPS J

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“…Baard et al [25] reported that a single dose of 0.2 to 0.3 mg/kg meclonazepam was curative in patients infected with S. haematobium or S. mansoni . Pharmacokinetic studies following single oral doses of meclonazepam and clonazepam show that plasma levels of the drugs corresponded to <3.5% of the original doses, and the proportion found in plasma tended to decrease as the dose increased [59]–[61]. Based on these figures, C max estimates for schistosomicidal doses of meclonazepam are likely to be < 600 nM, below the concentrations that affect schistosomes in culture.…”

Section: Resultsmentioning

confidence: 99%

Molecular Cloning and Characterization of Novel Glutamate-Gated Chloride Channel Subunits from Schistosoma mansoni

et al. 2013

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Cys-loop ligand-gated ion channels (LGICs) mediate fast ionotropic neurotransmission. They are proven drug targets in nematodes and arthropods, but are poorly characterized in flatworms. In this study, we characterized the anion-selective, non-acetylcholine-gated Cys-loop LGICs from Schistosoma mansoni. Full-length cDNAs were obtained for SmGluCl-1 (Smp_096480), SmGluCl-2 (Smp_015630) and SmGluCl-3 (Smp_104890). A partial cDNA was retrieved for SmGluCl-4 (Smp_099500/Smp_176730). Phylogenetic analyses suggest that SmGluCl-1, SmGluCl-2, SmGluCl-3 and SmGluCl-4 belong to a novel clade of flatworm glutamate-gated chloride channels (GluCl) that includes putative genes from trematodes and cestodes. The flatworm GluCl clade was distinct from the nematode-arthropod and mollusc GluCl clades, and from all GABA receptors. We found no evidence of GABA receptors in S. mansoni. SmGluCl-1, SmGluCl-2 and SmGluCl-3 subunits were characterized by two-electrode voltage clamp (TEVC) in Xenopus oocytes, and shown to encode Cl−-permeable channels gated by glutamate. SmGluCl-2 and SmGluCl-3 produced functional homomers, while SmGluCl-1 formed heteromers with SmGluCl-2. Concentration-response relationships revealed that the sensitivity of SmGluCl receptors to L-glutamate is among the highest reported for GluCl receptors, with EC50 values of 7–26 µM. Chloride selectivity was confirmed by current-voltage (I/V) relationships. SmGluCl receptors are insensitive to 1 µM ivermectin (IVM), indicating that they do not belong to the highly IVM-sensitive GluClα subtype group. SmGluCl receptors are also insensitive to 10 µM meclonazepam, a schistosomicidal benzodiazepine. These results provide the first molecular evidence showing the contribution of GluCl receptors to L-glutamate signaling in S. mansoni, an unprecedented finding in parasitic flatworms. Further work is needed to elucidate the roles of GluCl receptors in schistosomes and to explore their potential as drug targets.

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“…Meclonazepam was only detected at 8% of its original concentration after 4 weeks at −4°C and −20°C after 4 weeks). Meclonazepam has also been shown to be unstable in plasma in glass, but not in polypropylene tubes at −20°C . These studies indicate that any future nitrobenzodiazepines are likely to be unstable and suggest that all NPS‐benzodiazepines should be investigated for stability and that they should all be collected in tubes containing fluoride oxalate (1%) and then stored at the lowest temperature possible (ideally −20°C or lower) before analysis.…”

Section: Nps‐benzodiazepine Stabilitymentioning

confidence: 98%

The emergence of new psychoactive substance (NPS) benzodiazepines: A review

Manchester

Lomas

Waters

et al. 2017

Drug Testing and Analysis

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The market for new psychoactive substances has increased markedly in recent years and there is now a steady stream of compounds appearing every year. Benzodiazepines consist of only a fraction of the total number of these compounds but their use and misuse has rapidly increased.Some of these benzodiazepines have only been patented, some of them have not been previously synthesised, and the majority have never undergone clinical trials or tests. Despite their structural and chemical similarity, large differences exist between the benzodiazepines in their pharmacokinetic parameters and metabolic pathways and so they are not easily comparable. As benzodiazepines have been clinically used since the 1960s, many analytical methods exist to quantify them in a variety of biological matrices and it is expected that these methods would also be suitable for the detection of benzodiazepines that are novel psychoactive substances. Illicitly obtained benzodiazepines have been found to contain a wide range of compounds such as opiates which presents a problem since the use of them in conjunction with each other can lead to respiratory depression and death. This review collates the available information on these benzodiazepines and provides a starting point for the further investigation of their pharmacokinetics which is clearly required.

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Plasma determination of 3-methylclonazepam by capillary gas chromatography

Cited by 17 publications

References 4 publications

Identifying Metabolites of Meclonazepam by High-Resolution Mass Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and Authentic Urine Samples

Identifying Metabolites of Meclonazepam by High-Resolution Mass Spectrometry Using Human Liver Microsomes, Hepatocytes, a Mouse Model, and Authentic Urine Samples

Molecular Cloning and Characterization of Novel Glutamate-Gated Chloride Channel Subunits from Schistosoma mansoni

The emergence of new psychoactive substance (NPS) benzodiazepines: A review

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