Paracetamol metabolism in chronic liver disease

Abstract

The plasma concentrations and urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates were measured in eight normal subjects, eight patients with mild liver disease and seven patients with severe liver disease following an oral dose of 1.5 g of paracetamol. The mean plasma paracetamol half-life was similar in normal subjects (2.43 h +/- 0.19) but was significantly prolonged in all patients with severe liver disease (4.25 h +/- 1.15:p = less than 0.001). Prolongation of the paracetamol half-life was related to reduced plasma albumin and increased prothrombin time. The mean ratios of plasma concentrations of unchanged paracetamol to paracetamol glucoronide and sulphate were significantly greater in patients with sever liver disease than the normal subjects. There were no significant differences in the overall 24-h urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates in the three groups. The glutathione conjugation of paracetamol did not seem to be impaired in patients with severe liver disease as evidence by the production of normal amounts of the cysteine and mercapturic acid conjugates. There is thus no evidence that they are at increased risk of hepatotoxicity when given a single therapeutic dose of paracetamol.

Pharmacokinetics/Pharmacodynamics of Acetaminophen Analgesia in Japanese Patients with Chronic Pain

“…The pharmacokinetics of APAP have been reported in patients with chronic renal failure, 17) portal hypertension, 20) and chronic liver disease. 21,22) In patients with these diseases, the APAP half-life was long compared with that in healthy volunteers. Patients with chronic pain tend to take analgesics over a long period.…”

Kinetics and metabolism of paracetamol and phenacetin.

“…Although it has been claimed that paracetamol metabolism is impaired in the elderly (Briant, Dorrington, Cleal & Williams, 1976), the mean plasma half-life (2.17 h) is well within the range reported in young adults by many investigators. The plasma paracetamol half-life is prolonged in chronic liver disease, but to a lesser extent than antipyrine and lignocaine, and overall its metabolism is quantitatively the same as in healthy subjects (Forrest, Finlayson, Adjepon-Yamoah & Prescott, 1977;Forrest, Adriaenssens, Finlayson & Prescott, 1979). Paracetamol metabolism is also impaired in severe paracetamol poisoning, and prolongation of the plasma half-life is then a reliable index of the severity of liver damage (Prescott & Wright, 1973).…”

The effect of acetaminophen nanoparticles on liver toxicity in a rat model

“…10 The main factor for this toxicity can be attributed to the toxic metabolite N-acetyl-p-benzo-quinone imine (NAPQI) produced in the liver by changing a small percentage (about 5%-10%) of the acetaminophen dose in the P450 cytochrome. 11,12 In this condition, glutathione rapidly changes this toxic material to cysteine and mercapturate. Mercapturate is a stable metabolite that gradually leaves the body.…”