title: Intravenous Administration of Stable-Labeled N-Acetylcysteine Demonstrates an Indirect Mechanism for Boosting Glutathione and Improving Redox Status.
abstract: There is an increasing interest in using N-acetylcysteine (NAC) as a treatment for neurodegenerative disorders to increase glutathione (GSH) levels and its redox status. The purpose of this study was to characterize the biosynthesis of NAC to GSH using a novel stable isotope-labeled technique, and investigate the pharmacodynamics of NAC in vivo. Female wild-type mice were given a single intravenous bolus dose of 150 mg kg(-1) stable-labeled NAC. Plasma, red blood cells (RBC), and brain tissues were collected at predesignated time points. Stable-labeled NAC and its metabolite GSH (both labeled and unlabeled forms) were quantified in blood and brain samples. Molar ratios of the reduced and oxidized forms of GSH (GSH divided by glutathione disulfide, redox ratio) were also determined. The elimination phase half-life of NAC was approximately 34 min. Both labeled and unlabeled GSH in RBC were found to increase; however, the area under the curve above baseline (AUCb0-280 ) of labeled GSH was only 1% of the unlabeled form. These data indicate that NAC is not a direct precursor of GSH. In addition, NAC has prolonged effects in brain even when the drug has been eliminated from systemic circulation.
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, Minnesota, 55455.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, 55455.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, Minnesota, 55455.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, 55455.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Coles
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, Minnesota, 55455.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, 55455.
authors.forename: Reena V
authors.initials: RV
authors.lastname: Kartha
authors.affiliation: Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, 55455.
authors.forename: Nardina
authors.initials: N
authors.lastname: Nash
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, Minnesota, 55455.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, 55455.
authors.forename: Usha
authors.initials: U
authors.lastname: Mishra
authors.affiliation: Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, 55455.
authors.forename: Troy C
authors.initials: TC
authors.lastname: Lund
authors.affiliation: Center for Orphan Drug Research, University of Minnesota, Minneapolis, Minnesota, 55455.|Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, 55455.
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002247:Carbon Isotopes; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009587:Nitrogen Isotopes; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011355:Prodrugs / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011897:Random Allocation; D014018:Tissue Distribution
chemical_list: D000975:Antioxidants; D002247:Carbon Isotopes; D009587:Nitrogen Isotopes; D018697:Nootropic Agents; D011355:Prodrugs; D005978:Glutathione; D000111:Acetylcysteine
keywords: N-acetylcysteine (NAC); glutathione (GSH); metabolism; metabolite kinetics; pharmacodynamics; preclinical pharmacokinetics; prodrugs; redox ratio; stable-label