The Pharmacokinetic Profile of Intravenous Paracetamol in Adult Patients Undergoing Major Surgery: A Population Analysis
K. Owens (1), P. Murphy (2), N. Medlicott (1), J. Kennedy (2), M. Zacharias (3), N. Curran (3), S. Chary (1), M. Thompson-Fawcett (4), D. Reith (4)
(1) School of Pharmacy, University of Otago, New Zealand; (2) University College Cork, Ireland; (3) Dunedin Hospital, New Zealand; (4) Dunedin School of Medicine, University of Otago, New Zealand
Objectives: Intravenous paracetamol is commonly used in the post operative period as part of multimodal analgesia following surgery.  Paracetamol is extensively metabolised in the liver by glucuronidation, sulfation and oxidation with less than 5% excreted unchanged in the urine.  The aim of the present study was to determine the pharmacokinetic profile of intravenous paracetamol in adult patients undergoing major surgery and determine the time course of metabolic changes during the postoperative period.
Methods:A total of 53 patients were included in the dataset (33 patients from Cork, Ireland, 20 patients from Dunedin, NZ); 28 of the patients were men, the median age (range) was 60 years (33-87) and the median weight (range) was 74 kg (54-129). Patients were given doses of either 1, 1.5 or 2 g of paracetamol by intravenous (IV) infusion. A combination of rich and sparse plasma and urine samples were collected for up to 6 days after surgery. The samples were analysed by high pressure liquid chromatography to determine the amount of paracetamol and its glucuronide and sulfate metabolites. The population pharmacokinetic analysis was performed using Phoenix NLME. Simultaneous modelling of parent paracetamol and its two primary metabolites, paracetamol-glucuronide and paracetamol-sulfate, was conducted to estimate parameters for volumes of distribution, metabolic and urinary clearance.
Results: 53 patients contributed to a total of 4386 observations (2115 plasma concentrations and 2271 urinary excreted amounts) for paracetamol, paracetamol glucuronide and paracetamol sulfate. The pharmacokinetics of parent paracetamol were best described by a 2-compartment model with IV infusion input and linear disposition. The central volume of distribution was found to be 12.45 L/70kg, peripheral volume of distribution of 28.33 L/70kg and a intercompartmental clearance of 29.99 L/h/70kg. A proportional inter-subject error model and proportional residual error model was used. Covariates investigated included age, weight, sex, time after surgery and duration of surgery.
Conclusions: Our preliminary PK findings demonstrated that following major surgery, there were apparent increases in the metabolic conversion to paracetamol-glucuronide and its urinary clearance. Preliminary results support approved dose recommendations of intravenous paracetamol in the postoperative period, as there was no evidence of paracetamol toxicity, or down regulation of metabolic enzymes involved in paracetamol glucuronidation and sulfation.
 Duggan ST, Scott LJ. Intravenous paracetamol (acetaminophen). Drugs. 2009;69:101-13.
 Forrest JAH, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet. 1982;7:93-107.