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Clinical Pharmacokinetics

, Volume 7, Issue 2, pp 93–107 | Cite as

Clinical Pharmacokinetics of Paracetamol

  • John A. H. Forrest
  • J. A. Clements
  • L. F. Prescott
Article

Summary

In therapeutic doses paracetamol is a safe analgesic, but in overdosage it can cause severe hepatic necrosis. Following oral administration it is rapidly absorbed from the gastrointestinal tract, its systemic bioavailability being dose-dependent and ranging from 70 to 90%. Its rate of oral absorption is predominantly dependent on the rate of gastric emptying, being delayed by food, propantheline, pethidine and diamorphine and enhanced by metoclopramide. Paracetamol is also well absorbed from the rectum. It distributes rapidly and evenly throughout most tissues and fluids and has a volume of distribution of approximately 0.9L/kg. 10 to 20% of the drug is bound to red blood cells.

Paracetamol is extensively metabolised (predominantly in the liver), the major metabolites being the sulphate and glucuronide conjugates. A minor fraction of drug is converted to a highly reactive alkylating metabolite which is inactivated with reduced glutathione and excreted in the urine as cysteine and mercapturic acid conjugates. Large doses of paracetamol (overdoses) cause acute hepatic necrosis as a result of depletion of glutathione and of binding of the excess reactive metabolite to vital cell constituents. This damage can be prevented by the early administration of sulfhydryl compounds such as methionine and N-acetylcysteine.

In healthy subjects 85 to 95% of a therapeutic dose is excreted in the urine within 24 hours with about 4, 55, 30, 4 and 4% appearing as unchanged paracetamol and its glucuronide, sulphate, mercapturic acid and cysteine conjugates, respectively. The plasma half-life in such subjects ranges from 1.9 to 2.5 hours and the total body clearance from 4.5 to 5.5ml/kg/min. Age has little effect on the plasma half-life, which is shortened in patients taking anticonvulsants. The plasma half-life is usually normal in patients with mild chronic liver disease, but is prolonged in those with decompensated liver disease.

Keywords

Paracetamol Gastric Emptying Phenacetin Glucuronide Conjugate Mercapturic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© ADIS Press Australasia Pty Ltd. 1982

Authors and Affiliations

  • John A. H. Forrest
    • 1
    • 2
  • J. A. Clements
    • 1
    • 2
  • L. F. Prescott
    • 1
    • 2
  1. 1.Department of Therapeutics and Clinical PharmacologyThe Royal InfirmaryEdinburghScotland
  2. 2.Department of PharmacyHeriot-Watt UniversityEdinburghUK

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