| Abstract: | Background and objectives: ESRD is associated with systemic oxidative stress, an important nontraditional risk factor for the development of cardiovascular disease. Since interventions aimed at reducing oxidative stress may be beneficial, we examined the pharmacokinetics and pharmacodynamics of the widely used antioxidant N-acetylcysteine (NAC) after oral administration in patients with ESRD.Design, setting, participants, & measurements: Twenty-four ESRD patients were randomly assigned to receive 600 or 1200 mg of sustained-release NAC orally every 12 hours for 14 days. Seven healthy control subjects received NAC 600 mg in the same manner. Blood samples were obtained on days 1 and 15 for determination of NAC pharmacokinetics and pharmacodynamics.Results: Significant dose-related increases in NAC plasma concentrations were observed in ESRD patients with no change in total clearance; a doubling of the dose resulted in a 2-fold increase in NAC area under the plasma concentration-time curve (AUC). However, NAC clearance was reduced by 90% in ESRD, leading to a 7-fold larger AUC and 13-fold longer half-life compared with healthy control subjects. NAC administration resulted in a significant reduction in total homocysteine plasma concentrations in ESRD and healthy subjects, but had no effect on several other oxidative stress markers.Conclusions: These findings indicate that the total clearance of oral NAC is significantly reduced in ESRD patients, leading to marked increases in systemic exposure, and suggest that NAC may have a limited role in the chronic treatment of oxidative stress-related illness.End-stage renal disease (ESRD) is associated with systemic oxidative stress, which is an important nontraditional risk factor for the development of cardiovascular disease (1), now the leading cause of morbidity and mortality in patients with ESRD (2). Consequently, interventions aimed at reducing oxidative stress may be beneficial in ESRD, ultimately lowering the rate of cardiovascular events and improving survival.N-Acetylcysteine (NAC) is an aminothiol-containing antioxidant that has been used therapeutically for five decades (3). It has been used extensively as a mucolytic agent, in the treatment of acetaminophen toxicity, as a cytoprotective agent during cancer chemotherapy, and in the prevention of contrast-induced nephropathy (3,4). The mechanism of NAC''s antioxidant activity likely stems from its oxygen free-radical scavenging properties and/or its role as a source of cysteine, necessary for the biosynthesis of glutathione (4,5). The utility of antioxidant compounds like NAC to suppress oxidative stress and exert sustained, long-term beneficial effects in humans is based on the premise that they can be administered chronically in doses that are safe, effective, and well-tolerated. The pharmacokinetic (PK) disposition of NAC has been studied in subjects with normal renal function (6–9), and during intermittent intravenous administration with hemodialysis in ESRD patients (10), while only limited NAC pharmacodynamic (PD) assessments (e.g., endothelial function and plasma concentrations of homocysteine, malondialdehyde, or asymmetric dimethylarginine) have been carried out in ESRD subjects without simultaneous PK determination (11–16). To date, NAC PK and PD have not been comprehensively evaluated in ESRD patients after multiple-dose oral administration, which represents the most practical and cost-effective route of administration for chronic therapeutic use. Thus, the purpose of this study was to examine the PK and PD of NAC after multiple-dose oral administration to patients with ESRD. |
