Metabolic stability studies of lead compounds supported by separation techniques and chemometrics analysis

Ulenberg, Szymon; Bączek, Tomasz

doi:10.1002/jssc.202000831

Cited by 3 publications

(2 citation statements)

References 96 publications

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“…Metabolic stability allows the assessment of how long a drug can be stable in a studied system, including in vitro and in vivo studies. Additionally, in silico approaches have been developed to predict in vitro half-life such as the StarDrop WhichP450 module software package [ 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

A Validated LC–MS/MS Assay for the Simultaneous Quantification of the FDA-Approved Anticancer Mixture (Encorafenib and Binimetinib): Metabolic Stability Estimation

et al. 2021

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The concurrent use of oral encorafenib (Braftovi, ENF) and binimetinib (Mektovi, BNB) is a combination anticancer therapy approved by the United States Food and Drug Administration (USFDA) for patients with BRAFV600E/V600K mutations suffering from metastatic or unresectable melanoma. Metabolism is considered one of the main pathways of drug elimination from the body (responsible for elimination of about 75% of known drugs), it is important to understand and study drug metabolic stability. Metabolically unstable compounds are not good as they required repetitive dosages during therapy, while very stable drugs may result in increasing the risk of adverse drug reactions. Metabolic stability of compounds could be examined using in vitro or in silico experiments. First, in silico metabolic vulnerability for ENF and BNB was investigated using the StarDrop WhichP450 module to confirm the lability of the drugs under study to liver metabolism. Second, we established an LC–MS/MS method for the simultaneous quantification of ENF and BNB applied to metabolic stability assessment. Third, in silico toxicity assessment of ENF and BNB was performed using the StarDrop DEREK module. Chromatographic separation of ENF, BNB, and avitinib (an internal standard) was achieved using an isocratic mobile phase on a Hypersil BDS C18 column. The linear range for ENF and BNB in the human liver microsome (HLM) matrix was 5–500 ng/mL (R2 ≥ 0.999). The metabolic stabilities were calculated using intrinsic clearance and in vitro half-life. Furthermore, ENF and BNB did not significantly influence each other’s metabolic stability or metabolic disposition when used concurrently. These results indicate that ENF and BNB will slowly bioaccumulate after multiple doses.

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Section: Introductionmentioning

confidence: 99%

A Validated LC–MS/MS Assay for the Simultaneous Quantification of the FDA-Approved Anticancer Mixture (Encorafenib and Binimetinib): Metabolic Stability Estimation

et al. 2021

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“…Drug metabolism is one of the main routes of drug elimination from body, and it also plays an increasingly important role in drug discovery and development. Identification of metabolite(s) of a potential drug candidate provides key information on drug efficacy and toxicological profiles [11][12][13]. Several studies on the metabolism of ligustilide have been performed.…”

Section: Introductionmentioning

confidence: 99%

Metabolic profiling of ligustilide and identification of the metabolite in rat and human hepatocytes by liquid chromatography combined with high‐resolution mass spectrometry

Tao

Liu

2020

J of Separation Science

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Ligustilide is one of the most abundant bioactive ingredients in Rhizoma Chuanxiong that has been widely prescribed for medicinal purposes in China. To better understand the disposition and action of ligustilide, it is necessary to investigate the metabolic profiles. The in vitro metabolism was elucidated through incubating ligustilide with human and rat hepatocytes at 37 • C. The incubation samples were collected at predefined time points to determine the metabolic stability. Upon metabolite identification and profiling, the incubation samples were analyzed by ultra-high-performance liquid chromatography combined with diode array detector and high-resolution mass spectrometry. The structures of the metabolites were characterized based on their mass spectrometry spectra, tandem mass spectrometry spectra, and fragmentation patterns. Ligustilide showed fast metabolism with high intrinsic clearance both in rat and human hepatocyte incubations. The half-lives of ligustilide in rat and human hepatocyte incubations were 8.0 and 15.0 min, respectively. Most of the parent (>90%) was biotransformed into the metabolites. Among these metabolites, M1 (senkyunolide I) was the major metabolite both in rat and human hepatocytes with the percentage of 42 and 70%, respectively. The metabolic pathways of ligustilide included epoxidation, epoxide hydrolysis, aromatization, hydroxylation, and glutathionylation. This work provided an overview of the metabolic profiles of ligustilide, which would be helpful for us to understand the action of this compound.

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Metabolic profiling of the fluorinated liquid-crystal monomer 1-ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl)benzene

Wang¹,

Yang

Zhang

et al. 2022

SSRN Journal

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Metabolic stability studies of lead compounds supported by separation techniques and chemometrics analysis

Cited by 3 publications

References 96 publications

A Validated LC–MS/MS Assay for the Simultaneous Quantification of the FDA-Approved Anticancer Mixture (Encorafenib and Binimetinib): Metabolic Stability Estimation

A Validated LC–MS/MS Assay for the Simultaneous Quantification of the FDA-Approved Anticancer Mixture (Encorafenib and Binimetinib): Metabolic Stability Estimation

Metabolic profiling of ligustilide and identification of the metabolite in rat and human hepatocytes by liquid chromatography combined with high‐resolution mass spectrometry

Metabolic profiling of the fluorinated liquid-crystal monomer 1-ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl)benzene

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