Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling

Han, Dong-Gyun; Seo, Seong-Wook; Choi, Eun Young; Kim, Min‐Soo; Yoo, Jin‐Wook; Jung, Yunjin; Yoon, In‐Soo

doi:10.1016/j.biopha.2022.113141

Cited by 11 publications

(1 citation statement)

References 72 publications

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“…The CL int,S9 can be scaled up to its corresponding whole-organ level by physiological scaling factors (122, 75.3, 78.8, and 7.68 mg S9/g organ for rat liver, rat intestine, human liver, and human intestine, respectively) (Han et al, 2022).…”

Section: In Vitro Metabolism Study In Hepatic and Intestinal S9 Fract...mentioning

confidence: 99%

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC‐MS/MS method: In vitro, in situ, and in vivo evaluations

Seo

Han

Baek

et al. 2023

Drug Development Research

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Alizarin (1,2-dihydroxyanthraquinone) is an anthraquinone reddish dye widely used for painting and textile dyeing. As the biological activity of alizarin has recently attracted increasing attention from researchers, its therapeutic potential as complementary and alternative medicine is of interest. However, no systematic research has been conducted on the biopharmaceutical and pharmacokinetic aspects of alizarin. Therefore, this study aimed to comprehensively investigate the oral absorption and intestinal/hepatic metabolism of alizarin using a simple and sensitive tandem mass spectrometry method developed and validated in-house. The present method for the bioanalysis of alizarin has merits, including a simple pretreatment procedure, small sample volume, and adequate sensitivity. Alizarin exhibited pHdependent moderate lipophilicity and low solubility with limited intestinal luminal stability. Based on the in vivo pharmacokinetic data, the hepatic extraction ratio of alizarin was estimated to be 0.165-0.264, classified as a low level of hepatic extraction. In an in situ loop study, considerable fractions (28.2%-56.4%) of the alizarin dose were significantly absorbed in gut segments from the duodenum to ileum, suggesting that alizarin may be classified as the Biopharmaceutical Classification System class II. An in vitro metabolism study using rat and human hepatic S9 fractions revealed that glucuronidation and sulfation, but not NADPHmediated phase I reactions and methylation, are significantly involved in the hepatic metabolism of alizarin. Taken together, it can be estimated that the fractions of oral alizarin dose unabsorbed from the gut lumen and eliminated by the gut and liver before reaching the systemic circulation are 43.6%-76.7%, 0.474%-36.3%, and 3.77%-5.31% of the dose, respectively, resulting in a low oral bioavailability of 16.8%. Therefore, the oral bioavailability of alizarin depends primarily on its chemical degradation in the gut lumen and secondarily on first-pass metabolism.

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Section: In Vitro Metabolism Study In Hepatic and Intestinal S9 Fract...mentioning

confidence: 99%

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC‐MS/MS method: In vitro, in situ, and in vivo evaluations

Seo

Han

Baek

et al. 2023

Drug Development Research

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A simple and sensitive high‐performance liquid chromatographic method combined with fluorescence detection for bioanalysis of scopoletin in rat plasma: Application to a pharmacokinetic study

Kim,

Han,

Yoon

2024

Biomedical Chromatography

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Scopoletin, a coumarin class natural phytoalexin, is present in medicinal plants such as noni (Morinda citrifolia). It exhibits diverse pharmacological properties, including antioxidant, anti‐hyperuricemic, and anti‐inflammatory effects. The objective of this study was to develop a novel HPLC‐fluorescence (HPLC‐FL) method for the quantitative analysis of scopoletin in the plasma and to investigate its pharmacokinetics in rats. Sample preparation involved a methanol‐based protein precipitation method, and chromatographic separation was conducted using a C18 column with an isocratic mobile phase composed of water and acetonitrile containing 0.1% trifluoroacetic acid. The eluent was detected using an FL detector set to optimized excitation/emission wavelengths of 337/453 nm. Method validation encompassed assessments of selectivity, linearity (1–500 ng/mL), precision, accuracy, recovery, matrix effect, and stability in accordance with the prevailing Food and Drug Administration (FDA) guidelines. The developed method was successfully applied for pharmacokinetic study in rats. To the best of our knowledge, this study is the first application of a simple and sensitive HPLC‐FL method for the quantification of scopoletin in a pharmacokinetic study. This method offers a promising alternative for preclinical pharmacokinetic investigations with appropriate modifications and validations and holds potential for clinical applications.

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Beneficial effects of resveratrol on diabetes mellitus and its complications: focus on mechanisms of action

Ahmadzadeh,

Aliabadi,

Mirheidari

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling

Cited by 11 publications

References 72 publications

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC‐MS/MS method: In vitro, in situ, and in vivo evaluations

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC‐MS/MS method: In vitro, in situ, and in vivo evaluations

A simple and sensitive high‐performance liquid chromatographic method combined with fluorescence detection for bioanalysis of scopoletin in rat plasma: Application to a pharmacokinetic study

Beneficial effects of resveratrol on diabetes mellitus and its complications: focus on mechanisms of action

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