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Purpose <p>Umbelliferone, one of the most widely distributed coumarins, has beneficial effects in the management of asthma, cardiovascular diseases, diabetes, hepatic/renal injury, and rheumatoid arthritis. This study aimed to quantitatively investigate extrahepatic phase II metabolism and hepatic/gut first-pass effects of umbelliferone using rat and human physiologically based pharmacokinetic (PBPK) models.</p> Methods <p>In vitro, in situ, and in vivo experimental data regarding biorelevant stability, protein binding, blood distribution, phase II tissue metabolism (glucuronidation and sulfation), intestinal permeability, and in vivo pharmacokinetics were obtained. Using these datasets, we developed rat and human PBPK models incorporating extrahepatic phase II metabolism and route-dependent gut extraction was developed.</p> Results <p>The rat PBPK model simulations aligned with the observed systemic exposure of intravenously and orally administered umbelliferone with an acceptable prediction accuracy of 0.964–1.29-fold errors. Moreover, human PBPK model simulations suggested that umbelliferone administered orally at doses of 100 and 500&#xa0;mg exhibited linear pharmacokinetic profiles with peak blood concentrations of 55.0 and 275 ng/mL, respectively, and an oral bioavailability of 9.49% in clinical settings.</p> Conclusion <p>The PBPK model can be used to predict clinical drug interactions with natural products containing umbelliferone. Furthermore, this study provides an alternative in silico tool to support decision-making during the development of phytochemical-based functional foods when significant phase II metabolism in the liver and other organs is anticipated.</p>

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Physiologically based pharmacokinetic modeling for umbelliferone in rats and humans: impact of extrahepatic phase II metabolism and hepatic/gut first-pass extraction on oral bioavailability and systemic disposition

  • 期刊论文

  • 发表日期：

    2025年9月11日

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  • Ji-Su Kong,
  • Seong-Wook Seo,
  • Taeyoung Kim,
  • Hyung Ryong Moon,
  • Jin-Wook Yoo,
  • Min-Soo Kim,
  • Hwayoung Yun,
  • Seonghwan Hwang,
  • Ee Taek Hwang,
  • Yunjin Jung,
  • In-Soo Yoon

摘要

Purpose

Umbelliferone, one of the most widely distributed coumarins, has beneficial effects in the management of asthma, cardiovascular diseases, diabetes, hepatic/renal injury, and rheumatoid arthritis. This study aimed to quantitatively investigate extrahepatic phase II metabolism and hepatic/gut first-pass effects of umbelliferone using rat and human physiologically based pharmacokinetic (PBPK) models.

Methods

In vitro, in situ, and in vivo experimental data regarding biorelevant stability, protein binding, blood distribution, phase II tissue metabolism (glucuronidation and sulfation), intestinal permeability, and in vivo pharmacokinetics were obtained. Using these datasets, we developed rat and human PBPK models incorporating extrahepatic phase II metabolism and route-dependent gut extraction was developed.

Results

The rat PBPK model simulations aligned with the observed systemic exposure of intravenously and orally administered umbelliferone with an acceptable prediction accuracy of 0.964–1.29-fold errors. Moreover, human PBPK model simulations suggested that umbelliferone administered orally at doses of 100 and 500 mg exhibited linear pharmacokinetic profiles with peak blood concentrations of 55.0 and 275 ng/mL, respectively, and an oral bioavailability of 9.49% in clinical settings.

Conclusion

The PBPK model can be used to predict clinical drug interactions with natural products containing umbelliferone. Furthermore, this study provides an alternative in silico tool to support decision-making during the development of phytochemical-based functional foods when significant phase II metabolism in the liver and other organs is anticipated.