Diclofenac and metabolite pharmacokinetics in children

Paediatric Anaesthesia - Tập 14 Số 6 - Trang 443-451 - 2004
Caroline D. van der Marel1, Brian J. Anderson2, Janne Rømsing3, Evelyne Jacqz‐Aigrain4, Dick Tibboel1
1Department of Paediatric Surgery, ErasmusMC-Sophia Rotterdam, The Netherlands.
2Department of Anaesthesiology, University of Auckland, New Zealand
3The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark
4Department of Paediatric Clinical Pharmacology, Robert Debre Hospital, Paris, France

Tóm tắt

SummaryBackground : 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.

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Tài liệu tham khảo

10.2165/00128072-200103110-00004

10.1034/j.1399-6576.2000.440312.x

10.1046/j.1460-9592.2001.00660.x

10.1093/bja/88.2.215

10.1111/j.1365-2044.1997.130-az0126.x

10.1111/j.1399-6576.1998.tb05320.x

10.1213/00000539-200301000-00015

Tawalbeh MI, 2001, Comparative study of diclofenac sodium and paracetamol for treatment of pain after adenotonsillectomy in children, Saudi Med J, 22, 121

10.1111/j.1365-2044.1993.tb06851.x

Walmsley AJ., 1997, Peri‐operative use of nonsteroidal anti‐inflammatory drugs in children, Anaesthesia, 52, 1120

10.1007/BF00315034

10.2165/00003088-199733030-00003

10.3109/03009748309099735

10.3109/00498257909042328

10.3109/00498257909042327

Bort R, 1996, Metabolism of aceclofenac in humans, Drug Metab Dispos, 24, 834

10.3109/03009747809097211

Landsdorp D, 1990, Pharmacokinetics of rectal diclofenac and its hydroxy metabolites in man, Int J Clin Pharmacol Ther Toxicol, 28, 298

10.2165/00003088-199630050-00001

Peters HP., 1983, The Ecological Implications of Body Size, 48, 10.1017/CBO9780511608551

10.1890/03-0757

10.1126/science.284.5420.1677

10.1046/j.1460-9592.2002.00616.x

10.2165/00003088-200038060-00004

10.1213/00000539-200202000-00007

10.1177/00912709922008254

10.2165/00003088-199121010-00002

10.2165/00003088-199121020-00003

10.1016/S0016-5107(85)71996-7

10.3109/03009747809097212

Kendall MJ, 1979, Factors affecting the pharmacokinetics of diclofenac sodium (Voltarol), Rheumatol Rehabil, 38

John VA., 1979, The pharmacokinetics and metabolism of diclofenac sodium (Voltarol) in animals and man, Rheumatol Rehabil, 22

10.1007/BF00568201

10.1007/BF00542178

10.1007/BF01993259

10.1016/S0009-9236(96)90210-6

10.1007/s002280100367

10.2165/00003088-199223060-00003

10.1046/j.1365-2125.2000.00231.x

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Thông tin xuất bản

Paediatric Anaesthesia

Tập 14 Số 6

443-451

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