Studies on Drug Metabolism by Use of Isotopes XX: Ion Cluster Technique for Detection of Urinary Metabolites of 1-Butyryl-4-cinnamylpiperazine by Mass Chromatography

Morishita, Shinichi; Baba, Shigeo; Nagase, Yuzo

doi:10.1002/jps.2600670606

Cited by 10 publications

(5 citation statements)

References 14 publications

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“…Regarding the metabolic analysis, the most observed biotransformation and the relative metabolites identified are in line with the limited data present in the literature. As per AP‐237, our results are in accordance with a study on rats and rabbits, where the main metabolic pathway was represented by the p ‐hydroxylation on the benzene ring in the cinnamyl moiety 22,23 . Concerning its methyl derivative, Hassanien et al found that the only metabolic route for the compound in human liver microsomes is the hydroxylation, which could occur on various positions, that is, on the cinnamyl chain, piperazine ring, or acyl chain 24…”

Section: Discussionsupporting

confidence: 91%

“…As per AP-237, our results are in accordance with a study on rats and rabbits, where the main metabolic pathway was represented by the p-hydroxylation on the benzene ring in the cinnamyl moiety. 22,23 Concerning its methyl derivative, Hassanien et al found that the only metabolic route for the compound in human liver microsomes is the hydroxylation, which could occur on various positions, that is, on the cinnamyl chain, piperazine ring, or acyl chain. 24 In 2020, Krotluski and colleagues observed that N-dealkylation and O-dealkylation or the combination of them were the F I G U R E 3 Metabolic pathway of benzimidazole opioids.…”

Section: Discussionmentioning

confidence: 99%

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Study of metabolism and potential toxicity of nine synthetic opioid analogs using the zebrafish larvae model

Murari,

Pesavento,

Greco

et al. 2023

Drug Testing and Analysis

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The use of novel psychoactive substances (NPSs) has dramatically increased worldwide, and among them, synthetic opioids are one of the fastest growing groups, where cinnamylpiperazines and 2‐benzylbenzimidazoles represent two of the most relevant subclasses. However, the data on their toxicity and metabolism are still limited. The aim of the present study was to evaluate the toxicity and metabolic pathways of some compounds belonging to these families, namely, AP‐237, 2‐methyl AP‐237, isotonitazene, flunitazene, etodesnitazene, metonitazene, metodesnitazene, N‐pyrrolidino etonitazene, and butonitazene. The study was performed using a zebrafish early life stages model. In fact, zebrafish (Danio rerio) embryos and larvae have recently been recognized as a suitable animal model in alternative to mammals, because they require less time and resources and do not need complex procedures for ethics approval. The cellular toxicity after a single administration was assessed at the fourth day post‐fertilization with acridine orange staining. Possible morphological defects were evaluated with a light microscope after 24 h of exposure to 1 μmol/L concentration of each drug. Subsequently, the larvae were euthanized and underwent analysis of drug metabolites using UPLC coupled to an Orbitrap high‐resolution mass spectrometer. High rates of morphological defects, as well as of cellular death, were detected, but no significant difference in mortality between treatment and control groups was observed. In addition, several metabolites, mainly produced through monohydroxylation, N‐dealkylation, and O‐dealkylation, were identified in the larvae extracts.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Study of metabolism and potential toxicity of nine synthetic opioid analogs using the zebrafish larvae model

Murari,

Pesavento,

Greco

et al. 2023

Drug Testing and Analysis

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“…Comparing these results to a metabolic study of AP‐237 by Morishita et al, the vast majority of metabolic transformations that occurred were consistent with the metabolic profile of AP‐238 34 …”

Section: Resultssupporting

confidence: 83%

Human metabolism and basic pharmacokinetic evaluation of AP‐238: A recently emerged acylpiperazine opioid

Brunetti

Berardinelli

Giorgetti

et al. 2023

Drug Testing and Analysis

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As a consequence of recently implemented legal restrictions on fentanyl analogs, a new generation of acylpiperazine opioids appeared on the illicit drug market. AP‐238 was the latest opioid in this series to be notified by the European Early Warning System in 2020 and was involved in an increasing number of acute intoxications. AP‐238 metabolism was investigated to provide useful markers of consumption. For the tentative identification of the main phase I metabolites, a pooled human liver microsome assay was performed. Further, four whole blood and two urine samples collected during post‐mortem examinations and samples from a controlled oral self‐administration study were screened for anticipated metabolites. In total, 12 AP‐238 phase I metabolites were identified through liquid chromatography‐quadrupole time‐of‐flight mass spectrometry in the in vitro assay. All of these were confirmed in vivo, and additionally, 15 phase I and five phase II metabolites were detected in the human urine samples, adding up to a total of 32 metabolites. Most of these metabolites were also detected in the blood samples, although mostly with lower abundances. The main in vivo metabolites were built by hydroxylation combined with further metabolic reactions such as O‐methylation or N‐deacylation. The controlled oral self‐administration allowed us to confirm the usefulness of these metabolites as proof of intake in abstinence control. The detection of metabolites is often crucial to documenting consumption, especially when small traces of the parent drug can be found in real samples. The in vitro assay proved to be suitable for the prediction of valid biomarkers of novel synthetic opioid intake.

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“…Initial studies on bucinnazine metabolism were reported in rats and rabbits where metabolites were identified using gas chromatography and isotope tracing techniques. , Seven main metabolites were found; 1-butyryl-4-(4-hydroxycinnamyl)piperazine, 1-cinnamylpiperazine, 1-(4-hydroxycinnamyl)piperazine, benzoic acid, hippuric acid, 4-hydroxybenzoic acid, and 4-hydroxyhippuric acid. , Both authors described the main bucinnazine metabolic pathway as through p- hydroxylation.…”

Section: Metabolismmentioning

confidence: 99%

“…40,41 Seven m a i n m e t a b o l i t e s w e r e f o u n d ; 1 -b u t y r y l -4 -( 4hydroxycinnamyl)piperazine, 1-cinnamylpiperazine, 1-(4hydroxycinnamyl)piperazine, benzoic acid, hippuric acid, 4hydroxybenzoic acid, and 4-hydroxyhippuric acid. 40,41 Both authors described the main bucinnazine metabolic pathway as through p-hydroxylation.…”

Section: ■ Metabolismmentioning

confidence: 99%

DARK Classics in Chemical Neuroscience: Bucinnazine

Resnik

Brandão

Alves

2021

ACS Chem. Neurosci.

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Bucinnazine (1-butyryl-4-cinnamylpiperazine) is a synthetic opioid recently discovered in heroin seized samples in the U.S and in Europe. It was first synthesized in the late 1960s and has been used for the treatment of cancer-associated chronic pain in China for many years. Bucinnazine is one of the most potent compounds among the series of piperazines, which also include other relevant compounds, such as MT-45, AD-1211, and 2-methyl-AP-237, a methylated derivative of bucinnazine. Bucinnazine is considered a μ-selective opioid, binding primarily to the μ-opioid receptor. However, bucinnazine also may share several characteristics with other piperazines, which act primarily on dopamine, serotonin, and norepinephrine neurotransmission. At the present, bucinnazine is not scheduled in the U.S., as it is not a therapeutic choice for the treatment of pain. Nevertheless, with the advent of the cryptocurrency and the easy access of substances on the Darknet, bucinnazine is a real threat to the public health. This review discusses the main aspects of bucinnazine's chemistry, pharmacology, and toxicology and brings attention to the risk of the presence of this opioid in seized samples. Further studies on bucinnazine are still required to better evaluate its toxicity mechanisms, potential for drug−drug interactions, and abuse liability. Such information will be of utmost importance to guide future policies concerning the legal status of bucinnazine in the U.S.

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Studies on Drug Metabolism by Use of Isotopes XX: Ion Cluster Technique for Detection of Urinary Metabolites of 1-Butyryl-4-cinnamylpiperazine by Mass Chromatography

Cited by 10 publications

References 14 publications

Study of metabolism and potential toxicity of nine synthetic opioid analogs using the zebrafish larvae model

Study of metabolism and potential toxicity of nine synthetic opioid analogs using the zebrafish larvae model

Human metabolism and basic pharmacokinetic evaluation of AP‐238: A recently emerged acylpiperazine opioid

DARK Classics in Chemical Neuroscience: Bucinnazine

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