Document Detail


Paracetamol and metabolite pharmacokinetics in infants.
MedLine Citation:
PMID:  12761605     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Caroline D van der Marel; Brian J Anderson; Richard A van Lingen; Nicholas H G Holford; Marien A L Pluim; Frank G A Jansman; John N van den Anker; Dick Tibboel
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Publication Detail:
Type:  Clinical Trial; Journal Article     Date:  2003-05-22
Journal Detail:
Title:  European journal of clinical pharmacology     Volume:  59     ISSN:  0031-6970     ISO Abbreviation:  Eur. J. Clin. Pharmacol.     Publication Date:  2003 Jul 
Date Detail:
Created Date:  2003-08-04     Completed Date:  2004-01-15     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  1256165     Medline TA:  Eur J Clin Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  243-51     Citation Subset:  IM    
Affiliation:
Department of Paediatric Surgery, Erasmus MC-Sophia, Dr. Molenwaterplein 60, 3016 GJ Rotterdam, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Acetaminophen / analogs & derivatives*,  blood,  metabolism*,  pharmacokinetics*,  therapeutic use,  urine
Analgesics, Non-Narcotic / metabolism*,  pharmacokinetics*,  therapeutic use
Female
Humans
Infant
Male
Metabolic Clearance Rate
Pain, Postoperative / drug therapy
Chemical
Reg. No./Substance:
0/Analgesics, Non-Narcotic; 10066-90-7/acetaminophen sulfate ester; 103-90-2/Acetaminophen; 16110-10-4/acetaminophen glucuronide
Comments/Corrections
Comment In:
Eur J Clin Pharmacol. 2004 Jun;60(4):297   [PMID:  15148556 ]

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