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CETP inhibitor evacetrapib enters mouse brain tissue.

Jasmine Phénix1,2, Jonathan Côté3,4, Denis Dieme3,4

  • 1Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.

Frontiers in Pharmacology
|August 3, 2023
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Summary

Cholesteryl ester transfer protein (CETP) inhibitors like evacetrapib may treat Alzheimer's disease. Evacetrapib crosses the blood-brain barrier, suggesting potential for treating brain cholesterol dysregulation in Alzheimer's disease.

Keywords:
Alzheimer’s diseasePBPK modelbraincholesterolcholesteryl ester transfer protein (CETP)evacetrapibinhibitorpharmacokinetic

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • High plasma cholesterol, particularly LDL-C, is linked to increased Alzheimer's disease risk.
  • Cholesteryl ester transfer protein (CETP) activity elevates LDL-C; reduced CETP activity correlates with cognitive benefits and lower Alzheimer's risk.
  • CETP inhibitors are effective at lowering CETP activity and LDL-C, suggesting potential therapeutic use for Alzheimer's disease.

Purpose of the Study:

  • To investigate the pharmacokinetic parameters of the CETP inhibitor evacetrapib in plasma, liver, and brain tissues.
  • To determine if evacetrapib can cross the blood-brain barrier.
  • To assess the potential of evacetrapib as a therapeutic agent for Alzheimer's disease.

Main Methods:

  • Pharmacokinetic analysis of evacetrapib in CETP transgenic mice.
  • Measurement of evacetrapib concentrations in plasma, liver, and brain tissues.
  • Intravenous administration of evacetrapib at a 40 mg/kg dose.

Main Results:

  • Evacetrapib was detected in brain tissue 0.5 hours after intravenous injection.
  • Evacetrapib crosses the blood-brain barrier in a non-linear fashion.
  • Pharmacokinetic parameters in plasma, liver, and brain were characterized.

Conclusions:

  • Evacetrapib successfully crosses the blood-brain barrier.
  • Evacetrapib shows potential as a candidate drug for treating Alzheimer's disease by addressing CETP-mediated cholesterol dysregulation.
  • Further research is warranted to explore evacetrapib's efficacy in Alzheimer's disease models.