title: Drug access to the central nervous system in Alzheimer's disease: preclinical and clinical insights.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by β-amyloid plaques and hyperphosphorylated tau tangles in the brain. Alongside these pathological lesions, there have been multiple reports of physical and biochemical alterations to the blood-brain barrier (BBB) in people with AD, potentially impacting on the ability of systemically-administered drugs to reach the brain parenchyma. Though there has been much research into the identification of these BBB alterations during AD, there are very few studies that have assessed the impact of such BBB changes on the ability of therapeutic agents to traverse the BBB. Due to their increased age-associated risk of chronic disease, most people with AD are prescribed multiple concurrent medications. In people with AD, the altered nature of the BBB could impact upon the disposition and therefore pharmacological effects of a wide range of medicines. This review therefore evaluates the impact of BBB alterations in AD on CNS drug exposure, along with relevant examples of preclinical and clinical studies that address this current issue. This review highlights that the CNS exposure of drugs is likely to differ between people with AD and healthy individuals, warranting further clinical investigations and the consideration to tailor dosing regimens in people with this neurodegenerative disorder.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
authors.forename: Dharmini C
authors.initials: DC
authors.lastname: Mehta
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Short
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Hilmer
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Nicolazzo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D058225:Plaque, Amyloid; D019338:Polypharmacy; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002491:Central Nervous System Agents; D026901:Membrane Transport Proteins; D062725:Tight Junction Proteins; D016875:tau Proteins