Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's disease

Scientific Reports
Kai Lun ChangPaul C Ho

Abstract

Pioglitazone is currently undergoing clinical trials for treatment of Alzheimer's disease (AD). However, poor brain penetration remains an obstacle to development of the drug for such intended clinical uses. In this study, we demonstrate that the inhibition of P-glycoprotein (P-gp) significantly increases brain penetration of pioglitazone, whereas inhibition of breast cancer resistance protein (BCRP) has little effect. We also investigate the stereoselectivity of pioglitazone uptake in the brain. When mice were dosed with racemic pioglitazone, the concentration of (+)-pioglitazone was 46.6% higher than that of (-)-pioglitazone in brain tissue and 67.7% lower than that of (-)-pioglitazone in plasma. Dosing mice with pure (+)-pioglitazone led to a 76% increase in brain exposure levels compared to those from an equivalent dose of racemic pioglitazone. Pure (+)-pioglitazone was also shown to have comparable amyloid-lowering capabilities to the racemic pioglitazone in an in vitro AD model. These results suggest that P-gp may act as a stereoselective barrier to prevent pioglitazone entry into the brain. Dosing with (+)-pioglitazone instead of the racemic mixture may result in higher levels of brain exposure to pioglitazone, thus pote...Continue Reading

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Citations

Feb 10, 2019·Journal of Clinical Pharmacy and Therapeutics·Gifty M Jojo, Gowthamarajan Kuppusamy
Jan 23, 2019·American Journal of Physiology. Endocrinology and Metabolism·Chih-Wei WuKay L H Wu
Nov 13, 2018·Journal of Cancer Research and Clinical Oncology·Christina K CramerMichael D Chan
Sep 3, 2019·Frontiers in Neuroscience·Francesca FioryFrancesco Oriente
Jan 8, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Amila OmeragicReina Bendayan
Apr 10, 2019·Current Treatment Options in Oncology·Christina K CramerGlenn J Lesser
Mar 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ana LopesCarla Fernandes
Jul 6, 2019·Journal of Diabetes and Metabolic Disorders·Gifty M JojoUday Krishna Baruah
Jan 24, 2021·Molecular Neurobiology·Anit Tyagi, Subbiah Pugazhenthi
Mar 31, 2021·Biomedical Chromatography : BMC·Noha M El ZaharMichael G Bartlett
Jul 13, 2021·Journal of Medicinal Chemistry·Sabine WillemsDaniel Merk
Oct 6, 2021·Food & Function·Dafne Velásquez-JiménezGustavo A González-Aguilar
Oct 21, 2020·Dementia and Geriatric Cognitive Disorders·Mario Muñoz-JiménezNatalia García-Casares

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Methods Mentioned

BETA
transgenic
ELISA

Software Mentioned

Analyst

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