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. 2023 Jul 18:14:1171937.
doi: 10.3389/fphar.2023.1171937. eCollection 2023.

CETP inhibitor evacetrapib enters mouse brain tissue

Jasmine Phénix  1   2 , Jonathan Côté  3   4 , Denis Dieme  3   4 , Sherilyn J Recinto  1   2   5 , Felix Oestereich  1   2   5 , Sasen Efrem  1   2 , Sami Haddad  3   4 , Michèle Bouchard  3   4 , Lisa Marie Munter  1   2   6
Affiliations

CETP inhibitor evacetrapib enters mouse brain tissue

Jasmine Phénix et al. Front Pharmacol. .

Abstract

High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer's disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer's disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer's disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease.

Keywords: Alzheimer’s disease; PBPK model; brain; cholesterol; cholesteryl ester transfer protein (CETP); evacetrapib; inhibitor; pharmacokinetic.

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Conflict of interest statement

LM received funds from New Amsterdam Pharma for a research project regarding CETP inhibitors independent from the work presented herein. This PK study was completed in its core prior to this funding. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic representation of the three-compartment model simulation for the semi-PBPK model. See also Table 1.
FIGURE 2
FIGURE 2
Evacetrapib concentration in plasma after a single intravenous injection of evacetrapib at six time points over a 24-h course. Symbols represent means ± SEM, n = 4 per time point. * depicts significant differences (p < 0.05) between the two doses.
FIGURE 3
FIGURE 3
Evacetrapib concentration in the liver after a single intravenous injection of evacetrapib. Symbols represent means ± SEM, n = 4 per time point. * depicts significant differences (p < 0.05) between the two doses.
FIGURE 4
FIGURE 4
Evacetrapib concentration in the brain. (A) Experimental values not corrected for residual blood. (B) Experimental values corrected for residual blood. Symbols represent means ± SEM, n = 4 per time point. * depicts significant differences (p < 0.05) between the two doses.
FIGURE 5
FIGURE 5
Semi-PBPK modeling of evacetrapib entering the brain. (A) Three-compartment model simulation of the plasma concentration at 40 mg/kg. Experimentally determined values are indicated by black circles. Different perfusion-limited models show different concentrations, with the best fit obtained with diffusion limitation and fitted PA and PBr. (B) Parameters for the plasma and peripheral compartments fitted to the plasma concentration at 40 mg/kg BW.
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