Pharmacokinetics of α-amanitin in mice using liquid chromatography-high resolution mass spectrometry and <i>in vitro</i> drug–drug interaction potentials

Park, Ria; Choi, Won-Gu; Lee, Min Seo; Cho, Yong‐Yeon; Lee, Joo Young; Kang, Han Chang; Sohn, Chang Hwan; Song, Im‐Sook; Lee, Hye Suk

doi:10.1080/15287394.2021.1944942

Cited by 13 publications

(2 citation statements)

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“…The abbreviations shown are as follows: T 1/2 (half-life), C max (the observed maximum concentration in plasma), AUC last (area under the concentration–time curve to the last time point), and V ss (volume of distribution at steady state). The PK parameters of α-amanitin in this rat study showed comparable values to those in mice and dogs [ 10 , 11 ].…”

Section: Resultssupporting

confidence: 53%

Investigation of In Vitro and In Vivo Metabolism of α-Amanitin in Rats Using Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometric Method

Lee

Choi

et al. 2022

Molecules

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The purpose of this study is to investigate the difference of in vitro–in vivo correlation of α-amanitin from clearance perspectives as well as to explore the possibility of extra-hepatic metabolism of α-amanitin. First, a liquid chromatography-quadrupole-time-of-flight-mass spectrometric (LC-qTOF-MS) method for α-amanitin in rat plasma was developed and applied to evaluate the in vitro liver microsomal metabolic stability using rat and human liver microsomes and the pharmacokinetics of α-amanitin in rat. The predicted hepatic clearance of α-amanitin in rat liver microsomes was quite low (5.05 mL/min/kg), whereas its in vivo clearance in rat (14.0 mL/min/kg) was close to the borderline between low and moderate clearance. To find out the difference between in vitro and in vivo metabolism, in vitro and in vivo metabolite identification was also conducted. No significant metabolites were identified from the in vivo rat plasma and the major circulating entity in rat plasma was α-amanitin itself. No reactive metabolites such as GSH-adducts were detected either. A glucuronide metabolite was newly identified from the in vitro liver microsomes samples with a trace level. A semi-mass balance study was also conducted to understand the in vivo elimination pathway of α-amanitin and it showed that most α-amanitin was mainly eliminated in urine as intact which implies some unknown transporters in kidney might play a role in the elimination of α-amanitin in rat in vivo. Further studies with transporters in the kidney would be warranted to figure out the in vivo clearance mechanism of α-amanitin.

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Section: Resultssupporting

confidence: 53%

Investigation of In Vitro and In Vivo Metabolism of α-Amanitin in Rats Using Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometric Method

Lee

Choi

et al. 2022

Molecules

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“…A hybrid QqQ linear ion‐trap is a less employed mass analyzer (Tanner et al, 2019). To date, LC‐HRMS is starting to be used for the pharmacokinetic studies of small molecules, for example, LC coupled with quadrupole in tandem with Orbitrap (Alkhateeb et al, 2020; Park et al, 2021; Qian et al, 2022; Wang, Wang, et al, 2019). The number of publications on this topic has been rising every year.…”

Section: Ms‐based Methods In the Analysis Of Small‐molecule Chemical ...mentioning

confidence: 99%

What is the role of current mass spectrometry in pharmaceutical analysis?

Khalikova

Jireš

Horáček

et al. 2023

Mass Spectrometry Reviews

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The role of mass spectrometry (MS) has become more important in most application domains in recent years. Pharmaceutical analysis is specific due to its stringent regulation procedures, the need for good laboratory/manufacturing practices, and a large number of routine quality control analyses to be carried out. The role of MS is, therefore, very different throughout the whole drug development cycle. While it dominates within the drug discovery and development phase, in routine quality control, the role of MS is minor and indispensable only for selected applications. Moreover, its role is very different in the case of analysis of small molecule pharmaceuticals and biopharmaceuticals. Our review explains the role of current MS in the analysis of both small‐molecule chemical drugs and biopharmaceuticals. Important features of MS‐based technologies being implemented, method requirements, and related challenges are discussed. The differences in analytical procedures for small molecule pharmaceuticals and biopharmaceuticals are pointed out. While a single method or a small set of methods is usually sufficient for quality control in the case of small molecule pharmaceuticals and MS is often not indispensable, a large panel of methods including extensive use of MS must be used for quality control of biopharmaceuticals. Finally, expected development and future trends are outlined.

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Identification of α-amanitin effector proteins in hepatocytes by limited proteolysis-coupled mass spectrometry

Kim,

Lee,

Kim

et al. 2023

Chemico-Biological Interactions

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Pharmacokinetics of α-amanitin in mice using liquid chromatography-high resolution mass spectrometry and in vitro drug–drug interaction potentials

Cited by 13 publications

References 50 publications

Investigation of In Vitro and In Vivo Metabolism of α-Amanitin in Rats Using Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometric Method

Investigation of In Vitro and In Vivo Metabolism of α-Amanitin in Rats Using Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometric Method

What is the role of current mass spectrometry in pharmaceutical analysis?

Identification of α-amanitin effector proteins in hepatocytes by limited proteolysis-coupled mass spectrometry

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