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Paracetamol and metabolite pharmacokinetics in infants
Caroline D van der Marel1, Brian J Anderson, Richard A van Lingen
1Department of Paediatric Surgery, Erasmus MC-Sophia, Dr. Molenwaterplein 60, 3016 GJ Rotterdam, The Netherlands.
Insights
Paracetamol metabolism in infants shows glucuronide clearance increases with age, while sulphate clearance remains constant. Renal clearance of paracetamol and its metabolites is dependent on urine flow rate.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Drug Metabolism
Background:
- Limited data exists on paracetamol (acetaminophen) metabolism in infants.
- Previous research focused on neonates or older children, leaving a gap in infant data.
- This study addresses the lack of information on paracetamol's metabolic pathways in infants.
Purpose of the Study:
- To investigate paracetamol (acetaminophen) metabolism and clearance in infants.
- To determine how age and formulation affect paracetamol metabolism in infants.
- To compare infant paracetamol metabolism to that of neonates and children.
Main Methods:
- Studied 47 infants receiving paracetamol (acetaminophen) via elixir or suppository post-surgery.
- Assayed serum paracetamol concentrations and collected urine samples over 24 hours.
- Utilized non-linear, mixed-effects models to estimate metabolite clearances.
Main Results:
- Glucuronide formation clearance increased with infant age (half-life of 8.09 months), while sulphate formation clearance did not.
- Renal clearance of paracetamol and its metabolites correlated with urine volume flow rate.
- Sulphate metabolism accounted for 50% of paracetamol clearance in infants.
Conclusions:
- Paracetamol (acetaminophen) glucuronide formation clearance matures with age in infants.
- Renal clearance of paracetamol and its metabolites is influenced by urine flow rate.
- Undetectable oxidative pathways in infants may contribute to lower hepatotoxicity risk compared to adults.
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.