In vitro and in vivo metabolism of 3-quinuclidinyl benzilate by high-resolution mass spectrometry

Uher, Martin; Mzik, Martin; Karasová, Jana Žďárová; Herman, David; Cechova, Lenka; Dlabková, Alžběta; Mrkvicová, Alena; Hroch, Miloš

doi:10.1016/j.jpba.2020.113519

Cited by 4 publications

(5 citation statements)

References 13 publications

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“…The BZ biotransformation pathway is based on phase I metabolism, showing N‐oxidation and hydroxylation(s) of BZ with subsequent O‐glucuronosylation, O‐methylation or their combination in phase II. In a work by Uher et al, 18 we reported 26 metabolites of BZ, with the highest number present in the urine. Both the liver and the kidney were proven to be metabolically active.…”

Section: Discussionmentioning

confidence: 82%

“…Only the parent compound was found in that tissue. A complete list of observed BZ metabolites, together with their specification, can be found in Uher et al 18 The BZ concentration in bile reached 94.2 ± 17.8 ng/ml 30 min after administration of 2 and 708.7 ± 202.6 mg/kg 30 min after administration of 10 mg/kg. This indicates that biliary excretion plays only a minor role.…”

Section: Discussionmentioning

confidence: 99%

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3‐Quinuclidinyl benzilate (agent BZ) toxicokinetics in rats

Dlabková

Herman

Cechova

et al. 2021

Basic Clin Pharma Tox

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3‐Quinuclidinyl benzilate (BZ) ranks among incapacitating military warfare agents. It acts as a competitive inhibitor on muscarinic receptors leading to non‐lethal mental impairment. The present study aimed to investigate toxicokinetics of BZ in rats. Moreover, BZ can be exploited to produce a pharmacological model of Alzheimer's disease; thus, this paper focuses mainly on the BZ distribution to the brain. Wistar rats were administered i.p. with BZ (2 and 10 mg/kg). The BZ concentration was determined using LC‐MS/MS in plasma, urine, bile, brain, kidney and liver. The sample preparation was based on a solid phase extraction (liquids) or protein precipitation (organ homogenates). The plasma concentration peaked at 3 min (204.5 ± 55.4 and 2185.5 ± 465.4 ng/ml). The maximal concentration in the brain was reached several minutes later. Plasma elimination half‐life was 67.9 ± 3.4 in the 2 mg/kg group and 96.6 ± 27.9 in the 10 mg/kg group. BZ concentrations remained steady in the brain, with slow elimination (t1/2 506.9 ± 359.5 min). Agent BZ is excreted mainly via the urine. Steady BZ concentration in the brain could explain the previously published duration of the significant impairment in passive avoidance tasks in rats after an injection of BZ.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

3‐Quinuclidinyl benzilate (agent BZ) toxicokinetics in rats

Dlabková

Herman

Cechova

et al. 2021

Basic Clin Pharma Tox

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“…It has been used as a hallucinogenic warfare agent and represents a health hazard, classified as an incapacitating agent. 134 The neurological effects caused by QNB are due to the fact that it easily crosses the BBB, as it is highly lipophilic and has a high degree of binding to plasma proteins and red blood cells. 135 It is a clear example that a compound with high potency is not synonymous with an effective drug.…”

Section: Resultsmentioning

confidence: 99%

Analysing the effect caused by increasing the molecular volume in M1-AChR receptor agonists and antagonists: a structural and computational study

Montejo-López,

Sampieri-Cabrera,

Nicolás-Vázquez

et al. 2024

RSC Adv.

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“…The quinuclidine moiety was found in the quinine structure as a natural product and in other drug candidates and medicines (Washio et al, 2001;Shaffer et al, 2007;Maruyama et al, 2008;Zhou et al, 2011;Uher et al, 2020). In this study, the concentrations of quinuclidine and the putative FMO1-mediated metabolite quinuclidine N-oxide were evaluated using fluorescence and ultraviolet monitoring by simple reversed-phase liquid chromatography with a conventional alkali-resistant octadecylsilane (C 18 ) column and an isocratic system of methanol in ammonium bicarbonate (pH 10) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Quinuclidine is a strongly basic compound with a pK a (base) of 11.1, which is higher than that of typical FMO substrates such as benzydamine [pK a (base) 9.5] and trimethylamine [pK a (base) 9.8] ( Taniguchi-Takizawa et al, 2021). Quinuclidine N-containing basic moieties are found in natural product quinine and its derivatives and have been introduced into some drug candidates that affect the nervous system or an antimuscarinic agent for overactive bladder treatment (Washio et al, 2001;Shaffer et al, 2007;Maruyama et al, 2008;Zhou et al, 2011;Uher et al, 2020), and these substances are probably eliminated partly through N-oxide formation. Some reports have suggested a role for FMO1 or FMO3 in the metabolic elimination of these drugs (Washio et al, 2001;Shaffer et al, 2007;Zhou et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

QuinuclidineN-Oxygenation Mediated by Flavin-Containing Monooxygenases 1 and 3 in Kidney and Liver Microsomes from Humans, Monkeys, Dogs, and Pigs

Shimizu,

Makiguchi,

Uno

et al. 2024

Drug Metab Dispos

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Flavin-containing monooxygenases (FMOs) are a family of enzymes that are involved in the oxygenation of heteroatom-containing molecules. In humans, FMO3 is the major hepatic form, whereas FMO1 is predominant in the kidneys. FMO1 and FMO3 were also identified in monkeys, dogs, and pigs. The predicted contribution of human FMO3 to drug candidate N-oxygenation could be estimated using the classic base dissociation constants of the N-containing moiety. A basic quinuclidine moiety was found in the natural quinine and medicinal products. Consequently, N-oxygenation of quinuclidine was evaluated using liver and kidney microsomes from humans, monkeys, dogs, and pigs as well as recombinant FMO1, FMO3, and FMO5 enzymes. Experiments using simple reversed-phase liquid chromatography with fluorescence monitoring revealed that recombinant FMO1 mediated quinuclidine N-oxygenation with a high capacity in humans. Moreover, recombinant FMO1, FMO3, and/or FMO5 in monkeys, dogs, and pigs exhibited relatively broad substrate specificity toward quinuclidine N-oxygenation. Kinetic analysis showed that human FMO1 efficiently, and pig FMO1 moderately, mediated quinuclidine N-oxygenation with high capacity, which is consistent with the reported findings for larger substrates readily accepted by pig FMO1 but excluded by human FMO1. In contrast, human FMO3-mediated quinuclidine N-oxygenation was slower than that of the typical FMO3 substrate trimethylamine. These results suggest that some species differences exist in terms of FMO-mediated quinuclidine N-oxygenation in humans and some animal models (monkeys, dogs, and minipigs); however, the potential for quinuclidine, which has a simple chemical structure, to be inhibited clinically by co-administered drugs should be relatively low, especially in human livers.

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In vitro and in vivo metabolism of 3-quinuclidinyl benzilate by high-resolution mass spectrometry

Cited by 4 publications

References 13 publications

3‐Quinuclidinyl benzilate (agent BZ) toxicokinetics in rats

3‐Quinuclidinyl benzilate (agent BZ) toxicokinetics in rats

Analysing the effect caused by increasing the molecular volume in M1-AChR receptor agonists and antagonists: a structural and computational study

QuinuclidineN-Oxygenation Mediated by Flavin-Containing Monooxygenases 1 and 3 in Kidney and Liver Microsomes from Humans, Monkeys, Dogs, and Pigs

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