CETP inhibitor evacetrapib enters mouse brain tissue

Jasmine Phénix; Jonathan Côté; Denis Dieme; Sherilyn J Recinto; Felix Oestereich; Sasen Efrem; Sami Haddad; Michèle Bouchard; Lisa Marie Munter

doi:10.3389/fphar.2023.1171937

CETP inhibitor evacetrapib enters mouse brain tissue

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

Authors

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

¹ Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
² Cell Information Systems Group, Montreal, QC, Canada.
³ Department of Environmental and Occupational Health, School of Public Health, Université de Montréal, Montreal, QC, Canada.
⁴ Public Health Research Center (CReSP), Université de Montréal, Montreal, QC, Canada.
⁵ Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
⁶ Centre de Recherche en Biologie Structurale (CRBS), Montreal, QC, Canada.

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.

Grants and funding

This work was funded by the Weston Brain Institute award RR172187, Canadian Institute of Health Research CIHR-PJT-162302 and CIHR-PJT-175306, and Alzheimer Society of Canada regular Research Grant 17-02, The Alzheimer's Association US AARG-21-852152 and was supported by the Fonds de Recherche du Québec—Santé FRQS research allocation FRQ-S 36571, the Canada Foundation of Innovation Leaders Opportunity Fund Grant 32565, and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants RGPIN-2015-04645 to LM. JP and FO received a stipend award from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives initiative. JP further received the Laszlo and Etelka Kollar Fellowship of the Faculty of Medicine and Health Sciences of McGill University. FO further received studentships through the Integrated Program in Neuroscience (IPN). SR received a CGS-Master’s award.