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Why we should be vigilant: drug cytotoxicity observed with in vitro transporter inhibition studies

Xiaowan Zheng1, Lei Diao, Sean Ekins

  • 1Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 N. Pine Street, Baltimore, MD 21201, United States.

Biochemical Pharmacology
|July 6, 2010
PubMed

Insights

Cytotoxicity, not direct interaction, can cause apparent drug transporter inhibition in vitro. This finding is crucial for accurate drug development and avoiding false positives in transporter assays.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Drug Discovery

Background:

  • In vitro drug-transporter inhibition assays often assume direct transporter interaction.
  • Alternative mechanisms reducing substrate uptake are less frequently investigated.
  • Solute carrier (SLC) transporters play vital roles in drug disposition and efficacy.

Purpose of the Study:

  • To investigate the link between drug transporter inhibition and drug cytotoxicity.
  • To evaluate the impact of cytotoxicity on in vitro assays for ASBT, OCTN2, and EAAT4 transporters.
  • To identify drugs where observed inhibition is due to cytotoxicity rather than direct transporter interaction.

Main Methods:

  • Selected 21 known ASBT or OCTN2 inhibitors for screening.
  • Assessed inhibitory potency against ASBT, OCTN2, and EAAT4 transporters in stable cell lines.
  • Evaluated drug cytotoxicity in parallel with transporter inhibition assays.
  • Utilized MDCK and HEK cell lines for transporter expression.

Main Results:

  • Twenty drugs exhibited apparent inhibition for OCTN2 and ASBT transporters.
  • Four dihydropyridine calcium channel blockers showed cytotoxicity in MDCK cells.
  • Cytotoxicity explained apparent OCTN2 inhibition for three drugs, reclassifying them as non-inhibitors.
  • Cytotoxicity moderately contributed to ASBT inhibition for these three drugs.
  • Three out of four drugs showing apparent EAAT4 inhibition had their effects explained by cytotoxicity.

Conclusions:

  • Drug cytotoxicity can be a significant mechanism causing false positives in in vitro transporter inhibition assays.
  • Cytotoxicity effects vary across different cell lines, impacting assay reliability.
  • Accurate assessment requires distinguishing direct transporter inhibition from cytotoxicity-induced effects.
  • This study highlights the importance of considering cytotoxicity in drug development and pharmacophore modeling.

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