Abstract
Gelsenicine, mainly isolated from Gelsemium elegans Benth., is one of the most toxic alkaloids. The lack of information on gelsenicine leads to inaccurate risk and poisoning evaluation. In this study, the metabolic profiling and toxicokinetics of gelsenicine was studied by ultra-high performance liquid chromatography (UPLC) with quadrupole time-of-flight (Q-ToF) and tandem mass spectrometry in rats after intraperitoneal (i.p., 40 μg/kg) and intragastric (i.g., 60 μg/kg) administration. After i.p. administration, the area under the curve (AUC), the apparent volume of distribution (V), and the total body clearance (CL/F) of gelsenicine in plasma were 3.79 μg/L h, 38.47 L/kg, and 11.87 mL/h kg, respectively. After i.g. administration, the corresponding values were slightly increased (5.49 μg/L h; 53.10 mL/kg, and 12.66 mL/h kg). The toxicokinetic results indicated that the hepatic first-pass effect was predominant after i.p. administration. The UPLC–Q-ToF–MS data revealed nine metabolites in plasma, urine, and bile which were largely obtained by demethylation, hydroxylation, acetylation and glycine conjugation. Metabolites were mainly excreted through urine and bile, most of which in urine was basically eliminated in 24 h. Molecular docking and liver microsome experiments further showed that gelsenicine was metabolized by cytochrome P450 3A4 and 3A5. Summarizing, the present study provides metabolic and toxicokinetic information on gelsenicine which in turn may help in future risk assessment and forensic identification after poisonings.
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Abbreviations
- LD 50:
-
Lethal dose 50%
- ED50:
-
50% Effective dose
- i.v. :
-
Intravenous administration
- i.p. :
-
Intraperitoneal administration
- i.g. :
-
Intragastrical administration
- NADPH:
-
β-Nicotinamide adenine dinucleotide phosphate
- CYP 450:
-
Cytochrome P450 enzyme
- LOQ:
-
Limit of quantitation
- LLOQ:
-
Lowest limit of quantification
- UPLC-Q-TOF:
-
Ultrahigh-performance liquid chromatography–quadrupole time-of-flight
- UPLC-MS/MS:
-
Ultra performance liquid chromatography–tandem mass spectrometry
- MRM:
-
Multiple reaction monitoring
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Acknowledgements
The authors acknowledge financial support from National Natural Science Foundation of China (nos. 81773691 and 81973696), and granted by Wenzhou Science and Technology Major Project, China (ZS2017018).
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal experiments complied with European Union Directive 2010/63/EU used for scientific purposes and were approved by the international laws on Laboratory Animal Center of Wenzhou Medical University (Wenzhou, China).
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**ang, Z., Qiu, J., He, X. et al. Toxicokinetics, in vivo metabolic profiling, and in vitro metabolism of gelsenicine in rats. Arch Toxicol 96, 525–533 (2022). https://doi.org/10.1007/s00204-021-03209-7
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DOI: https://doi.org/10.1007/s00204-021-03209-7