Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer’s and Parkinson’s diseases
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BACKGROUND: A number of peptide incretin receptor agonists (IRAs) show promise as therapeutics for Alzheimer's disease (AD) and Parkinson's disease (PD). Transport across the blood-brain barrier (BBB) is one way for IRAs to act directly within the brain. To determine which IRAs are high priority candidates for treating these disorders, we have studied their brain uptake pharmacokinetics. METHODS: C-labeled albiglutide, dulaglutide, DA5-CH, or tirzepatide and used multiple-time regression analyses to measure brain kinetics up to 1 hour. For those IRAs failing to enter the brain 1 h after intravenous injection, we also investigated their ability to enter over a longer time frame (i.e., 6 h). RESULTS: Albiglutide and dulaglutide had the fastest brain uptake rates within 1 hour. DA5-CH appears to enter the brain rapidly, reaching equilibrium quickly. Tirzepatide does not appear to cross the BBB within 1 h after iv injection but like albumin, did so slowly over 6 h, presumably via the extracellular pathways. CONCLUSIONS: We find that IRAs can cross the BBB by two separate processes; one that is fast and one that is slow. Three of the four IRAs investigated here have fast rates of transport and should be taken into consideration for testing as AD and PD therapeutics as they would have the ability to act quickly and directly on the brain as a whole.
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Tirzepatide has been reported to exhibit slower brain uptake in murine models.
“Tirzepatide, in particular, has been reported to exhibit slower brain uptake in murine models, 51”
From Neurodegeneration and Stroke After Semaglutide and Tirzepatide in Patients With Diabetes and Obesity (2025) · cites this paper as [51]
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- Authors
- Rhea, E. M., Babin, A., Thomas, P., Omer, M., Weaver, R., Hansen, K., Banks, W. A., & Talbot, K.
- Affiliations
- University of Washington (US)
- VA Puget Sound Health Care System (US)
- Loma Linda University Medical Center (US)
- Corresponding author
- Rhea, Elizabeth M.
- Talbot, Konrad
- Venue
- Tissue Barriers
- Publisher
- Informa UK Limited
- Published
- 2023-12-14
- Volume
- 12
- Issue
- 4
- Pages
- 2292461-2292461
- ISSN
- 2168-8362 (ISSN-L)
- 2168-8370
- PMC
- PMC11583597
- OpenAlex
- W4389799894
- Cited by
- 81
- References
- 81
- Citations by year
- 2026: 31 · 2025: 31 · 2024: 19
- FWCI
- 8.35
- Type
- journal article
- Language
- en
- Update notices
- correction (2026-03-09)
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/mark/1.0/ (vor)
- Locations
- Tissue Barriers (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Research and Development
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- albiglutide, dulaglutide, tirzepatide, incretin receptor agonists, blood-brain barrier transport, Alzheimer's disease, Parkinson's disease, peptide delivery, radiolabeled peptides
- MeSH terms
- Alzheimer Disease, Animals, Blood-Brain Barrier, Brain, Glucagon-Like Peptides, Immunoglobulin Fc Fragments, Male, Parkinson Disease, Recombinant Fusion Proteins, Mice, Glucagon-Like Peptide 1
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