Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 58, Issue 2, Pages 158-167Publisher
WILEY
DOI: 10.1002/jcph.1008
Keywords
N-acetylcysteine; Parkinson's disease; glutathione; neurodegeneration; pharmacokinetics; oxidative stress; antioxidant; magnetic resonance spectroscopy; phase 2; clinical study
Categories
Funding
- Parkinson's UK
- NIH [R01AG039396]
- University of Minnesota Foundation
- National Institute of Biomedical Imaging and Bioengineering (NIBIB) [P41 EB015894]
- Institutional Center Cores for Advanced Neuroimaging award [P30 NS076408]
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000114]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000114, UL1TR002494] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [P41EB015894] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P30NS076408] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG039396] Funding Source: NIH RePORTER
- Parkinson"
- s UK [K-1401] Funding Source: researchfish
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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 H-1-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.
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