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

Abstract

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.

Intravenous N-acetylcysteine for preventing contrast-induced nephropathy: A randomised trial

“…The dose employed was fixed at 600 mg twice daily in accordance with the bioavailability of the drug [29]. No Nacetylcysteine adverse effects were found in our study, in contrast with the data reported by Baker et al after the employment of a larger dose and with a different administration rate (RAPPID study) [12].…”

“…A low intravenous dose of N-acetylcysteine was employed during the 6 h before the procedure for two different reasons: Firstly, the coronary angiography was considered to be an emergency procedure in our patients, so it made it impossible to administer the drug during the day before, and secondly, due to the metabolite terminal half-life described in previous pharmacokinetic studies [28][29][30].…”

Primary graft dysfunction after liver transplantation: From pathogenesis to prevention

“…N-acetylcysteine, on the other hand, acts by replenishing glutathione stores and is likely to be more effective, but it has the disadvantage of reducing tissue extraction of oxygen in cirrhotic patients. 99 A recent study has shown a possible role for SAMe, if given perioperatively, in attenuating reperfusion injury. 98 SAMe is an endogenous methyl group donor, a precursor of adenosine and glutathione.…”

Oxidative stress as a component of chromium-induced cytotoxicity in rat calvarial osteoblasts

“…The results can be attributed to direct interaction of NAC with ROS or enhancement of cellular GSH synthesis. On the other hand, NAC has some side effects, including being prooxidant, suppressing respiratory burst, and causing a toxic ammonia accumulation in case of liver problems (Holdiness 1991;Jones et al 1997). More attention should be paid to the selection of the indication and dose of NAC in clinical application.…”