Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease.
OBJECTIVE
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.


METHODS
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.
Nolin
Thomas D
TD
University of Pittsburgh School of Pharmacy, Department of Pharmacy & Therapeutics, Pittsburgh, PA 15261, USA. nolin@pitt.edu
Ouseph
Rosemary
R
Himmelfarb
Jonathan
J
McMenamin
M Elizabeth
ME
Ward
Richard A
RA
D000111:Acetylcysteine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D003692:Delayed-Action Preparations; D015536:Down-Regulation; D005260:Female; D006207:Half-Life; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D011446:Prospective Studies; D016896:Treatment Outcome; D014481:United States
D000975:Antioxidants; D015415:Biomarkers; D003692:Delayed-Action Preparations; D006710:Homocysteine; D000111:Acetylcysteine