Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress

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Abstract

Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using 1H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration–time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

Original languageEnglish (US)
Pages (from-to)158-167
Number of pages10
JournalJournal of Clinical Pharmacology
Volume58
Issue number2
DOIs
StatePublished - Feb 2018

Bibliographical note

Funding Information:
Financial support was provided by Parkinson's UK, NIH R01AG039396, and the University of Minnesota Foundation. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health award number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We acknowledge Laurie Hovde for measurement of 4-HNE, catalase, and MDA. Financial support was provided by Parkinson's UK, NIH R01AG039396, and the University of Minnesota Foundation. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health award number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. None of the authors have any relevant conflicts of interest to disclose.

Funding Information:
Financial support was provided by Parkinson’s UK, NIH R01AG039396, and the University of Minnesota Foundation. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health award number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2017, The American College of Clinical Pharmacology

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • N-acetylcysteine
  • Parkinson's disease
  • antioxidant
  • clinical study
  • glutathione
  • magnetic resonance spectroscopy
  • neurodegeneration
  • oxidative stress
  • pharmacokinetics
  • phase 2

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