Metabolism of N-acetyl-l-cysteine Some structural requirements for the deacetylation and consequences for the oral bioavailability

Sjödin, Karin; Nilsson, Elisibeth; Hallberg, Anders; Tunek, Anders

doi:10.1016/0006-2952(89)90677-1

Cited by 89 publications

(40 citation statements)

References 21 publications

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“…In the rodent studies discussed above [22,25], NAC was infused intravenously. Unlike TAU, NAC undergoes extensive first-pass hepatic metabolism when administered orally, resulting in low systemic bioavailability [37,38]. The partial effect of NAC on endogenous insulin clearance suggests that effective NAC concentrations were reached in the liver.…”

Section: Discussionmentioning

confidence: 99%

Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men

2007

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Aims/hypothesis Antioxidants have been shown to ameliorate lipid-induced impairment of insulin action and beta cell function, both in vitro and in animal studies. The aim of the present study was to examine the effects of two orally administered antioxidants, N-acetylcysteine (NAC) and taurine (TAU), on lipotoxicity in humans. Methods Nine non-diabetic men, who were either overweight or obese, underwent three studies each, 4-6 weeks apart, in random order: (1) i.v. infusion of saline for 48 h (SAL); (2) i.v. infusion of Intralipid and heparin for 48 h to mimic chronic elevation of plasma NEFA (IH); and (3) IH infusion for 48 h with concurrent oral NAC (IH+NAC). Six men underwent similar studies except for study 3, where instead of NAC they received a 2 week pretreatment with oral TAU (IH+TAU). Results For both the NAC and TAU studies, a 48 h IH infusion alone without antioxidant impaired insulin sensitivity (S I , 63% and 62% of SAL in NAC and TAU studies, respectively) and beta cell function, as evidenced by a reduction in disposition index (DI, 55% and 54% of SAL in NAC and TAU studies, respectively). NAC failed to prevent the lipid-induced increase in levels of the plasma oxidative stress marker malondialdehyde and did not prevent the lipid-induced reduction in S I or DI, whereas TAU completely prevented the rise in malondialdehyde and decreased 4-hydroxynonenal, and significantly improved S I (91% of SAL) and DI (81% of SAL). Conclusions/interpretation Oral TAU ameliorates lipidinduced functional beta cell decompensation and insulin resistance in humans, possibly by reducing oxidative stress.ClinicalTrials.gov ID no. NCT0018873

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Section: Discussionmentioning

confidence: 99%

Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men

2007

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“…Increases in GSH and cysteine levels were also observed 30 min after NACA was administered to mice (unpublished). The possible mechanism for NACA to facilitate the supply of cysteine may be by readily reaching the cell's interior and becoming deacetylated to form cysteine, as occurs for the parent molecule, N-acetylcysteine [32].…”

Section: Discussionmentioning

confidence: 99%

Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12

et al. 2005

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Oxidative stress plays an important role in neuronal cell death associated with many different neurodegenerative conditions such as cerebral ischemia and Parkinson's disease. Elevated levels of glutamate are thought to be responsible for CNS disorders through various mechanisms causing oxidative stress induced by a nonreceptor-mediated oxidative pathway which blocks cystine uptake and results in depletion of intracellular glutathione (GSH). The newly designed amide form of N-acetylcysteine (NAC), N-acetylcysteine amide (NACA), was assessed for its ability to protect PC12 cells against oxidative toxicity induced by glutamate. NACA was shown to protect PC12 cells from glutamate (Glu) toxicity, as evaluated by LDH and MTS assays. NACA prevented glutamate-induced intracellular GSH loss. In addition, NACA restored GSH synthesis in a Glu (10 mM) plus buthionine -sulfoximine (BSO) (0.2 mM)-treated group, indicating that the intracellular GSH increase is independent of g-GSC (g-glutamylcysteinyl synthetase). The increase in levels of reactive oxygen species (ROS) induced by glutamate was significantly decreased by NACA. Measurement of malondialdehyde (MDA) showed that NACA reduced glutamate-induced elevations in levels of lipid peroxidation by-products. These results demonstrate that NACA can protect PC12 cells against glutamate cytotoxicity by inhibiting lipid peroxidation, and scavenging ROS, thus preserving intracellular GSH. D

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“…10 Its bioavailability is low after oral administration in humans 10 and rats, 15 presumably because of extensive metabolism in the gastrointestinal tract and liver. NAC is deacetylated in the liver in the rat, mouse and human tissue in vitro 16 and it is also rapidly metabolized to cysteine and inorganic sulphate in the gastrointestinal tract of the rat. 17 However, such data may not be relevant to the in vivo situation in patients with cirrhosis because the existence of a cirrhotic liver alters liver blood¯ow by the hepatic resistance; the presence of collaterals and plasma protein concentrations may also be different in a disease state.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of N‐acetylcysteine are altered in patients with chronic liver disease

Jones

Jarvie

Simpson

et al. 1997

Aliment Pharmacol Ther

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Background: The threshold plasma paracetamol concentration at which N‐acetylcysteine (NAC) treatment is recommended to treat paracetamol poisoning in a patient with induced liver enzymes (for example, with chronic liver disease or taking anticonvulsant drugs) is 50% lower than in a patient without induced liver enzymes. More patients with chronic liver disease might therefore be expected to be exposed to NAC treatment than previously. In addition, there is increasing use of NAC in patients with chronic liver disease for multiorgan failure or hepatorenal syndrome. Little is known of NAC's pharmacokinetic properties in patients with cirrhosis. Aim: The aim was to determine if the pharmacokinetics of NAC are altered by chronic liver disease. Subjects and methods: NAC was given intravenously in a dose of 600 mg over 3 min to nine patients with biopsy‐proven cirrhosis (Child's grade; 1 A, 4 B, 4 C; aetiology: 7 alcohol‐related, 1 primary biliary cirrhosis, 1 secondary biliary stenosis) and six healthy matched controls. Venous blood was taken at 20, 40, 60 and 90 min then at 2, 3, 4, 6, 8 and 10 h after NAC administration. Serum NAC was estimated by HPLC. The data were normalized to a standard body weight of 70 kg. Results: The area under the serum concentration–time curve was increased (152.34 mg/L.h ± 50.38 s.d.) in cirrhotics compared with normal controls; (93.86 mg/L.h ± 9.60 s.d.) (P < 0.05). The clearance of NAC was reduced in patients with chronic liver disease (4.52 L/h ± 1.87 s.d.) compared with controls (6.47 L/h ± 0.78; P < 0.01). Conclusions: Increased vigilance for untoward anaphylactoid reactions is necessary in cirrhotics as they may have higher plasma NAC concentrations. Further studies to determine the optimum dosage regimen in such patients are required.

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Metabolism of N-acetyl-l-cysteine Some structural requirements for the deacetylation and consequences for the oral bioavailability

Cited by 89 publications

References 21 publications

Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men

Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men

Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12

Pharmacokinetics of N‐acetylcysteine are altered in patients with chronic liver disease

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