Pharmacokinetics of intravenous paracetamol in children and adolescents under major surgery

The aim of this study was to describe the pharmacokinetics of paracetamol (acetaminophen) and to get primary information on its metabolism after first indicated intravenous administration of paracetamol in children and adolescents undergoing major surgery. About 4 weeks after the last chemotherapy, seven children and adolescents (five osteosarcoma, two Ewing tumors) received paracetamol infusion (median: 15.0 mg/kg) for analgesia. Sparse serum (37 samples; 4-7 per patient) and urine samples (27 samples; 0-15 per patient) were analyzed for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, paracetamol-mercapturate and paracetamol-cysteine using capillary electrophoresis. Nonlinear mixed-effect models were used to describe the pharmacokinetics of paracetamol in plasma. Pharmacokinetics of paracetamol after intravenous administration was best described by a two-compartment model with clearance of 13.2 l/h per 70 kg (between-subject variability: 30%), intercompartmental clearance of 45.7 l/h per 70 kg (both parameters standardized to a 70-kg person using allometric "1/4 power models"), central volume of distribution of 13.2 l per 70 kg (between-subject variability: 71%) and peripheral volume of distribution of 33.0 l per 70 kg. Paracetamol, the glucuronide- and sulfate conjugates as well as cysteine and mercapturic acid conjugates, both products of oxidative pathways of paracetamol, were excreted in urine. Surgery, with all its potential influencing factors, together with chemotherapy given about 4 weeks previously do not seem to have a major impact on the pharmacokinetic behavior and the between-subject variability of paracetamol after intravenous administration.