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Paracetamol and metabolite pharmacokinetics in infants

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

Data concerning metabolism of paracetamol in infants are scant. Previous studies have examined urinary metabolite recovery rates after a single dose of paracetamol in either neonates (<6 weeks) or children (3–9 years). There are no studies investigating infants.

Methods

Infants (n=47) undergoing major craniofacial surgery were given paracetamol 19–45 mg/kg 6-, 8-, or 12-hourly as either elixir or suppository formulation for postoperative analgesia, after a loading dose of 33–59 mg/kg rectally during the operation. Serum was assayed for paracetamol concentration in 40 of these infants at 5, 8, 11, 14, 17 and 20 h postoperatively. Urine samples were collected every 3 h for 24 h in 15 of these infants. The clearances of paracetamol to glucuronide and sulphate metabolites as well as the urinary clearance of unmetabolised paracetamol were estimated using non-linear, mixed-effects models.

Results

Mean (±SD) age and weight of the patients were 11.8±2.5 months and 9.1±1.9 kg. Clearances of paracetamol to paracetamol-glucuronide (%CV) and to paracetamol-sulphate were 6.6 (11.5) l/h and 7.5 (11.5) l/h respectively, standardised to a 70-kg person using allometric '1/4 power' models. Glucuronide formation clearance, but not sulphate formation, was related to age and increased with age from a predicted value in a neonate of 2.73 l/h/70 kg to a mature value of 6.6 l/h/70 kg with a maturation half-life of 8.09 months. Urine clearance of paracetamol-glucuronide, paracetamol-sulphate and unchanged paracetamol (%CV) were, respectively, 2.65, 3.03 and 0.55 (28) l/h/70 kg. The urine clearance of unchanged paracetamol and metabolites was related to urine volume flow rate. Clearance attributable to pathways other than these measured in urine was not identifiable. The glucuronide/sulphate formation clearance ratio was 0.69 at 12 months of age. Sulphate metabolism contributed 50% towards paracetamol clearance.

Conclusion

Glucuronide formation clearance increases with age in the infant age range but sulphate formation does not. Renal clearance of paracetamol and its metabolites increases with urine flow rate. This and other studies show that paracetamol metabolism to glucuronide appears to be similar in infants and children, but in adults is increased in comparison with children. Oxidative pathways were undetectable in this infant study and may explain, in part, the reduced incidence of hepatotoxicity in infants.

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Authors and Affiliations

  1. Department of Paediatric Surgery, Erasmus MC-Sophia, The Netherlands

    Caroline D. van der Marel & Dick Tibboel

  2. Intensive Care Unit Pediatric Surgery, Erasmus MC-Sophia, Dr. Molenwaterplein 60, 3015 GJ , Rotterdam, The Netherlands

    Dick Tibboel

  3. Department of Pharmacy, Erasmus MC-Sophia, The Netherlands

    Marien A. L. Pluim

  4. Department of Paediatrics, Erasmus MC-Sophia, The Netherlands

    John N. van den Anker

  5. Department of Anaesthesia, University Hospital Maastricht, The Netherlands

    Brian J. Anderson

  6. Department of Paediatrics, Isala Clinics Zwolle, The Netherlands

    Richard A. van Lingen

  7. Department of Pharmacy, Isala Clinics Zwolle, The Netherlands

    Frank G. A. Jansman

  8. Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand

    Nicholas H. G. Holford

  9. Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA

    John N. van den Anker

  10. Department of Pediatrics and Pharmacology, George Washington University Medical Center, Washington, DC, USA

    John N. van den Anker

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  1. Caroline D. van der Marel
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  2. Brian J. Anderson
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Correspondence to Dick Tibboel.

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van der Marel, C.D., Anderson, B.J., van Lingen, R.A. et al. Paracetamol and metabolite pharmacokinetics in infants. Eur J Clin Pharmacol 59, 243–251 (2003). https://doi.org/10.1007/s00228-003-0608-0

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  • DOI: https://doi.org/10.1007/s00228-003-0608-0

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