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Drug interaction study of flavonoids toward OATP1B1 and their 3D structure activity relationship analysis for

Xiaoqing Fan1, Jie Bai1, Minwan Hu1

  • 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.

Toxicology
|April 8, 2020
PubMed

Insights

Certain flavonoids inhibit OATP1B1, a transporter linked to liver injury. These compounds may protect against drug-induced liver damage by blocking OATP1B1 activity, offering insights into food-drug interactions.

Area of Science:

  • Pharmacology
  • Hepatology
  • Natural Products Chemistry

Background:

  • Organic anion transporting polypeptide 1B1 (OATP1B1) is a liver transporter implicated in drug-induced liver injury (DILI).
  • Flavonoids, abundant in natural products, are known to cause transporter-mediated drug-drug interactions (DDIs).
  • Identifying OATP1B1 inhibitors is crucial for mitigating DILI and understanding herb-drug interactions.

Purpose of the Study:

  • To screen 99 flavonoids for OATP1B1 inhibition.
  • To evaluate the hepatoprotective effects of identified flavonoids against bosentan-induced liver injury.
  • To elucidate the structural basis for OATP1B1 inhibition by flavonoids.

Main Methods:

  • In vitro OATP1B1 inhibition assays using OATP1B1-HEK293 cells.
  • Assessment of OATP1B1-mediated methotrexate uptake and cytotoxicity.
  • Pharmacokinetic studies in rats to determine the effect on methotrexate AUC0-t.
  • Bosentan-induced rat liver injury model to evaluate hepatoprotective effects.
  • Pharmacophore modeling to identify key structural features for OATP1B1 inhibition.

Main Results:

  • Eight flavonoids (biochanin A, hispidulin, isoliquiritigenin, isosinensetin, kaempferol, licochalcone A, luteolin, sinensetin) showed significant OATP1B1 inhibition (>50%).
  • These flavonoids reduced OATP1B1-mediated methotrexate influx and cytotoxicity, and increased methotrexate AUC0-t in rats (28.27%-82.71%).
  • In a bosentan-induced liver injury model, the eight flavonoids decreased serum total bile acid and liver bosentan concentrations, with kaempferol showing the most significant reduction (54.17%).

Conclusions:

  • Flavonoids can inhibit OATP1B1, potentially alleviating DILI by reducing transporter-mediated drug uptake.
  • Kaempferol demonstrates significant hepatoprotective effects in a bosentan-induced liver injury model, likely via OATP1B1 inhibition.
  • Structural features like hydrogen bond acceptors and donors are critical for flavonoid potency against OATP1B1, aiding in predicting herb-drug interaction risks.
Keywords:
DILIFlavonoidsInhibitionOATP1B1Structure-activity relationships

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