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P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate

Yongming Jia1, Zhihao Liu2, Changyuan Wang2

  • 1Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.

Toxicology and Applied Pharmacology
|July 6, 2016
PubMed

Insights

Resveratrol enhances methotrexate absorption in the intestine and reduces kidney elimination by inhibiting key transporters. This improves methotrexate-induced kidney damage without increasing intestinal toxicity.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Toxicology

Background:

  • Methotrexate (MTX) is a vital chemotherapy agent with narrow therapeutic index.
  • MTX pharmacokinetics and toxicity are influenced by absorption and elimination pathways.
  • Understanding drug interactions is crucial for optimizing MTX therapy.

Purpose of the Study:

  • To investigate the effect of resveratrol (Res) on methotrexate (MTX) pharmacokinetics.
  • To elucidate the molecular mechanisms underlying Res-MTX interactions.
  • To evaluate the impact of Res on MTX-induced toxicity.

Main Methods:

  • In vivo and in vitro studies using rat models and cell lines (MDR1-MDCK, MRP2-MDCK, hOAT1/3-HEK293).
  • Assessment of MTX intestinal absorption and renal clearance.
  • Evaluation of MTX transport inhibition by Res.
  • Analysis of MTX-induced cytotoxic and nephrotoxic effects.

Main Results:

  • Resveratrol significantly increased MTX intestinal absorption.
  • Resveratrol inhibited MTX efflux via MDR1 and MRP2 transporters.
  • Resveratrol decreased MTX renal clearance by inhibiting OAT1 and OAT3 transporters.
  • Resveratrol ameliorated MTX-induced nephrotoxicity without exacerbating intestinal damage.

Conclusions:

  • Resveratrol alters MTX pharmacokinetics by enhancing intestinal absorption and reducing renal elimination.
  • Resveratrol's mechanism involves the inhibition of P-gp, MRP2, OAT1, and OAT3 transporters.
  • Resveratrol demonstrates potential in mitigating MTX-induced nephrotoxicity while maintaining therapeutic efficacy.
Keywords:
Drug-drug interactionMethotrexateResveratrolTransporter

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