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Fenofibrate down-regulates renal OCT2-mediated organic cation transport via PPARα-independent pathways

Nithi Asavapanumas1, Suticha Kittayaruksakul, Paranee Meetam

  • 1Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.

Drug Metabolism and Pharmacokinetics
|April 5, 2012
PubMed

Insights

Fenofibrate reduces renal OCT2 activity by decreasing transporter numbers, independent of PPARα. This finding is crucial for understanding drug interactions and kidney function in hyperlipidemia patients.

Area of Science:

  • Pharmacology
  • Nephrology
  • Molecular Biology

Background:

  • Fibrate drugs, PPARα agonists, treat hyperlipidemia.
  • Renal OCT2 is vital for drug and metabolite transport.
  • Understanding fibrate effects on OCT2 is clinically relevant.

Purpose of the Study:

  • To investigate the impact of fibrate drugs on renal OCT2 activity.
  • To determine the mechanism and pathway (PPARα-dependent or independent) of fenofibrate's effect on OCT2.

Main Methods:

  • Utilized Chinese hamster ovary (CHO-K1) cells expressing rabbit OCT2, LLC-PK1 cells, and mouse renal cortical slices.
  • Assessed [³H]-MPP⁺ uptake in the presence of fenofibrate, clofibrate, WY14643, and GW6471.
  • Analyzed kinetic parameters (Jmax, Kt) and protein synthesis inhibition.

Main Results:

  • Fenofibrate significantly inhibited OCT2 activity in cell systems and renal slices.
  • This inhibition was PPARα-independent, as demonstrated by GW6471.
  • Fenofibrate reduced maximal transport (Jmax) by decreasing OCT2 membrane expression, not affecting affinity (Kt) or protein synthesis.

Conclusions:

  • Fenofibrate decreases renal OCT2 activity through a PPARα-independent mechanism.
  • The reduction in activity is due to fewer functional OCT2 transporters at the cell membrane.
  • Findings highlight potential drug-drug interactions and impact on renal drug clearance.

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