Modelling paracetamol urine metabolites

Abstract

Introduction Glucuronidation is immature in neonates and sulphation is the dominant metabolic pathway (glucuronide/sulphate 0.34). Adult glucuronide/sulphate ratios (+2) are believed to occur at 12 years (1). Different UDP‐glucuronosyltransferases, the rate‐limiting enzyme in neonates, mature at different rates: that responsible for bilirubin metabolism, for example, within the first 3 months of life. These enzymes are regulated not only by ontogenic, but also by genetic processes. Paracetamol clearance approaches adult rates at 1 year, when standardised to an allometric 3/4 power model (2). Urinary metabolites in 11‐month‐old children were investigated to determine metabolic pathway predominance at this age for paracetamol.Methods Ethical committee approval was granted and informed consent from parents/caregivers was obtained for each study child. Children (n = 158) nursed in PICU after craniosyntosis surgery were given regular paracetamol (LD 40 mg/kg, MD 20 mg·kg−1 6–8 h over 24 h). Serial serum concentrations were measured in 150 children (3). Urine was collected at 3 h intervals for 24 h and assayed for paracetamol, paracetamol glucuronide and paracetamol sulphate in 15 children.Data were analysed using differential equations for a 7 compartment model with the first order conditional estimate method using ADVAN 6, Tol = 5 of NONMEM V. Data were pooled with another study (2) to characterise oral bioavailability.Results Children had a mean age 11.8 SD 2.6 months and weight 9.1 SD 1.9 kg. Oral paracetamol bioavailability was low compared to rectal. due to nasogastric loss and vomiting. Sulphate metabolite clearance was 2.85 l·h−1·70kg−1 while glueuronide metabolite clearance was 6.07 l·h−1·70kg−1. Unmetabolised paracetamol urinary clearance (3.65 l·h−1·70kg−1) was unexpectedly large and was related to urine production with an exponential function. We were unable to estimate other metabolite (e.g. mercaptopurine/cysteine metabolites from glutathione) clearances.Discussion The glucuronide/sulphate ratio of approximately 2 that is described in children aged 12 years (1) was reached by the age of 1 year. Earlier reports suggested that this ratio be attained slowly during childhood. Our data suggests that maturation of the glucuronide system for paracetamol is more rapid during the first year than previously assumed.