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Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration
H Quiding1, G L Olsson, L O Boreus
1Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Insights
Rectal codeine administration in infants and young children shows that by 6 months of age, infants can metabolize codeine to morphine. This study measured drug levels to assess pediatric pharmacokinetics.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Drug Metabolism
Background:
- Codeine is a widely used analgesic in pediatric populations.
- Understanding codeine metabolism and pharmacokinetics in infants is crucial for safe and effective pain management.
- Rectal administration is a common route for pediatric drug delivery.
Purpose of the Study:
- To investigate the pharmacokinetics of rectally administered codeine in infants and young children.
- To determine the extent of codeine metabolism to morphine in different pediatric age groups.
- To assess the impact of repeated dosing on drug concentrations.
Main Methods:
- Codeine suppositories (4 mg for 6-10 month olds, 8 mg for 3-4 year olds) were administered rectally.
- Plasma concentrations of codeine and its metabolite morphine were measured using Gas Chromatography/Mass Spectrometry (GC/MS).
- Pharmacokinetic parameters including half-life and AUC were calculated; repeated dosing was studied in older children.
Main Results:
- Codeine and morphine plasma concentrations were measured over 5 hours post-administration.
- The morphine to codeine concentration ratio was higher in infants (4.3%) compared to children (1.6%), suggesting age-dependent differences in glucuronidation.
- Repeated dosing in children did not significantly alter plasma concentrations, and infants as young as 6 months showed capacity for codeine O-demethylation.
Conclusions:
- Infants aged 6 months and older can effectively O-demethylate codeine to morphine.
- Rectal codeine administration results in measurable plasma levels of both codeine and morphine in pediatric patients.
- Pharmacokinetic profiles suggest potential differences in drug metabolism related to age and body weight.
Abstract:
1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol l-1 in the younger and 309, 251 and 169 nmol l-1 in the older patients. The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l-1 and 6.8, 5.5 and 2.8 nmol l-1 respectively. One patient in each age group had no detectable amounts of morphine. 3. In the four children, the rectal dose was repeated 6-hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4. In the infants the mean plasma half-lives of codeine and morphine were 2.6 and 2.5 h. The two infants with the lowest body weights had the longest half-lives. 5. The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6. We conclude that at the age of 6 months infants are capable of O-demethylating codeine to morphine.