Antagonizing with Flumazenil after Sedation with Midazolam in Upper Gastrointestinal Endoscopy

Mizuno, Ju; Matsuki, Michiko; Gouda, Yoshinori; Tanimoto, Mitsune; Hanaoka, Kazuo

doi:10.2185/jjrm.52.823

Cited by 1 publication

(6 citation statements)

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“…The metabolic path and rate of a drug are closely related to the distribution of drugs in the body, the rate of elimination, and the period of efficacy [11,17,19]. A study of drug metabolites is of great significance for the proper application of drugs [18].…”

Section: Discussionmentioning

confidence: 99%

“…A study of drug metabolites is of great significance for the proper application of drugs [18]. The mixed reaction of a test drug solution with animal tissue slices, homogeneous solution, separation and extraction components, liver cells, etc., can be used for metabolic reaction research [11,17,19]. Tandem mass spectrometry was used to determine the identity of the flumazenil relative derivatives in the liver homogenate and hepatic microsomal bio-systems [23,24].…”

Section: Discussionmentioning

confidence: 99%

“…For metabolism, a drug molecule is gradually transformed into more polar substances by metabolic enzymes, so the Rt chromatography times of the metabolites are faster than those of the original drug molecule [11,17,19]. In a rat liver homogenate solution, flumazenil was bio-transformed to M1, a methyl transesterification product, with a molecular weight of 289, which less 14 molecular weight of the parent drug (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…Because the homogenized solution of rat liver retains all liver enzyme functions, the influence of a liver matrix on the matrix liver disturbance of trace metabolite analysis may also be significant [13]. The metabolic rate and products of the rat liver microsomes and rat liver homogenates to flumazenil were compared to determine the metabolic mechanism of liver enzymes to flumazenil [11,17].…”

Section: Discussionmentioning

confidence: 99%

“…Previous pre-clinical studies have suggested that an increased synaptic GABA concentration enhances the affinity of GABAA receptors for benzodiazepine ligands [16,17]. Flumazenil antagonizes the benzodiazepine binding site of the GABA/benzodiazepine receptor complex (BZR) in the CNS, thereby preventing chloride channel opening and inhibiting neuronal hyperpolarization [11,18].…”

Section: Introductionmentioning

confidence: 99%

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Identification of Hepatic Metabolites of [<sup>18</sup>F]Flumazenil and Evaluation of its Application in Neuroimaging

Chen¹,

Chiu²,

Farn³

et al. 2023

Preprint

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Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

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