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Diclofenac and metabolite pharmacokinetics in children.
Paediatr Anaesth. 2004 Jun; 14(6):443-51.PA

Abstract

BACKGROUND

Data concerning metabolism of diclofenac in children are limited to intravenous and enteric coated oral formulations. There are no data examining diclofenac or its hydroxyl metabolite pharmacokinetics after rectal administration in children.

METHODS

Infants (n = 26) undergoing tonsillectomy were given diclofenac 2 mg.kg(-1) followed by 1 mg.kg(-1) 8 h as suppository formulation for postoperative analgesia. Serum was assayed for diclofenac, 4'-hydroxydiclofenac and 5'-hydroxydiclofenac concentrations during the procedure and 1, 2 and 4 h postoperatively. The formation clearances of diclofenac to hydroxyl metabolites were estimated using nonlinear mixed effects models. A single compartment, first order absorption and first order elimination model was used to describe diclofenac pharmacokinetics. Published data from 11 children given enteric-coated diclofenac tablets were used to assess relative bioavailability.

RESULTS

Mean (sd) age and weight of the patients were 4.5 (1.5) years and 20.5 (4.1) kg. The formation clearance to 4'-hydroxydiclofenac (% CV) and to 5'-hydroxydiclofenac were 8.41 (8.1) and 3.41 (113) l.h(-1) respectively, standardized to a 70 kg person using allometric '1/4 power' models. Clearance by other routes contributed 33.0 (64) l.h(-1) 70 kg(-1). Elimination clearance of hydroxyl metabolites was fixed at 27.5 l.h(-1) 70 kg(-1). The volumes of distribution of parent diclofenac and its hydroxyl metabolite were 22.8 (19.0) and 45.3 (l.70) kg(-1). The suppository formulation had an absorption half-life of 0.613 (33.2) h with a lag time of 0.188 (24.9) h. Interoccasion variability of formation clearance to 4'-hydroxydiclofenac, diclofenac volume of distribution, absorption half-time and lag time for the suppository was 36%, 55%, 14% and 119%, respectively. The relative bioavailability of the suppository compared with an enteric-coated tablet was 1.26.

CONCLUSION

The formation clearance of the active metabolite 4'-hydroxydiclofenac contributed 19% of total clearance (44.82 l.h(-1) 70 kg(-1)). The rectum is a suitable route for administration of diclofenac in children 2-8 year of age and was associated with a higher relative bioavailabilty than enteric-coated tablets and an earlier maximum concentration (50 vs. 108 min). This pharmacokinetic profile renders diclofenac suppository a suitable formulation for short duration surgery.

Authors+Show Affiliations

Department of Paediatric Surgery, ErasmusMC-Sophia Rotterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15153204

Citation

van der Marel, Caroline D., et al. "Diclofenac and Metabolite Pharmacokinetics in Children." Paediatric Anaesthesia, vol. 14, no. 6, 2004, pp. 443-51.
van der Marel CD, Anderson BJ, Rømsing J, et al. Diclofenac and metabolite pharmacokinetics in children. Paediatr Anaesth. 2004;14(6):443-51.
van der Marel, C. D., Anderson, B. J., Rømsing, J., Jacqz-Aigrain, E., & Tibboel, D. (2004). Diclofenac and metabolite pharmacokinetics in children. Paediatric Anaesthesia, 14(6), 443-51.
van der Marel CD, et al. Diclofenac and Metabolite Pharmacokinetics in Children. Paediatr Anaesth. 2004;14(6):443-51. PubMed PMID: 15153204.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diclofenac and metabolite pharmacokinetics in children. AU - van der Marel,Caroline D, AU - Anderson,Brian J, AU - Rømsing,Janne, AU - Jacqz-Aigrain,Evelyne, AU - Tibboel,Dick, PY - 2004/5/22/pubmed PY - 2004/9/3/medline PY - 2004/5/22/entrez SP - 443 EP - 51 JF - Paediatric anaesthesia JO - Paediatr Anaesth VL - 14 IS - 6 N2 - BACKGROUND: Data concerning metabolism of diclofenac in children are limited to intravenous and enteric coated oral formulations. There are no data examining diclofenac or its hydroxyl metabolite pharmacokinetics after rectal administration in children. METHODS: Infants (n = 26) undergoing tonsillectomy were given diclofenac 2 mg.kg(-1) followed by 1 mg.kg(-1) 8 h as suppository formulation for postoperative analgesia. Serum was assayed for diclofenac, 4'-hydroxydiclofenac and 5'-hydroxydiclofenac concentrations during the procedure and 1, 2 and 4 h postoperatively. The formation clearances of diclofenac to hydroxyl metabolites were estimated using nonlinear mixed effects models. A single compartment, first order absorption and first order elimination model was used to describe diclofenac pharmacokinetics. Published data from 11 children given enteric-coated diclofenac tablets were used to assess relative bioavailability. RESULTS: Mean (sd) age and weight of the patients were 4.5 (1.5) years and 20.5 (4.1) kg. The formation clearance to 4'-hydroxydiclofenac (% CV) and to 5'-hydroxydiclofenac were 8.41 (8.1) and 3.41 (113) l.h(-1) respectively, standardized to a 70 kg person using allometric '1/4 power' models. Clearance by other routes contributed 33.0 (64) l.h(-1) 70 kg(-1). Elimination clearance of hydroxyl metabolites was fixed at 27.5 l.h(-1) 70 kg(-1). The volumes of distribution of parent diclofenac and its hydroxyl metabolite were 22.8 (19.0) and 45.3 (l.70) kg(-1). The suppository formulation had an absorption half-life of 0.613 (33.2) h with a lag time of 0.188 (24.9) h. Interoccasion variability of formation clearance to 4'-hydroxydiclofenac, diclofenac volume of distribution, absorption half-time and lag time for the suppository was 36%, 55%, 14% and 119%, respectively. The relative bioavailability of the suppository compared with an enteric-coated tablet was 1.26. CONCLUSION: The formation clearance of the active metabolite 4'-hydroxydiclofenac contributed 19% of total clearance (44.82 l.h(-1) 70 kg(-1)). The rectum is a suitable route for administration of diclofenac in children 2-8 year of age and was associated with a higher relative bioavailabilty than enteric-coated tablets and an earlier maximum concentration (50 vs. 108 min). This pharmacokinetic profile renders diclofenac suppository a suitable formulation for short duration surgery. SN - 1155-5645 UR - https://www.unboundmedicine.com/medline/citation/15153204/Diclofenac_and_metabolite_pharmacokinetics_in_children_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1155-5645&date=2004&volume=14&issue=6&spage=443 DB - PRIME DP - Unbound Medicine ER -