title: Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's disease.
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 potentially improving the development of pioglitazone treatment of AD.
authors.affiliation: 1] Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore [2] Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Kai Lun
authors.initials: KL
authors.lastname: Chang
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Hai Ning
authors.initials: HN
authors.lastname: Pee
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Shili
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Ho
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone