Summary
The effect of treatment with diflunisal on the steady-state pharmacokinetics of indomethacin has been studied in 16 healthy volunteers.
The steady-state plasma concentration and AUC of indomethacin were significantly increased two- to threefold during treatment with diflunisal and its total clearance and total volume of distribution were significantly decreased. The urinary recovery of total indomethacin (unchanged+glucuronides) was significantly lower during administration of diflunisal, whereas excretion of the indomethacin metabolites desmethylindomethacin and desbenzoylindomethacin and their glucuronides was not significantly altered. The results can be explained by selective inhibition of glucuronidation of unchanged indomethacin by diflunisal.
The interaction appears clinically relevant as potentially dangerous side effects of indomethacin are related to its plasma concentration.
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References
Alvan G, Orme M, Bertilsson L, Ekstrand R, Palmer L (1975) Pharmacokinetics of indomethacin. Clin Pharmacol Ther 18: 364–373
Bayne WF, East T, Dye D (1981) High-pressure liquid chromatographic method with postcolumn, in-line hydrolysis and fluorometric detection for indomethacin in biological fluids. J Pharm Sci 70: 458–459
Duggan DE, Hogans AF, Kwan KC, McMahon FG (1972) The metabolism of indomethacin in man. J Pharmacol Exp Ther 181: 563–575
Ferry DG, Ferry DM; Moller PW, McQueen EG (1974) Indomethacin estimation in plasma and serum by electron capture gas chromatography. J Chromatogr 89: 110–112
Hucker HB, Zacchei AG, Cox SV, Brodie DA, Cantwell NHR (1966) Studies on the absorption, distribution and excretion of indomethacin in various species. J Pharmacol Exp Ther 153: 237–249
Kwan KC, Breault GO, Umbenhauer ER, McMahon FG, Duggan DE (1976) Kinetics of indomethacin absorption, elimination and enterohepatic circulation in man. J Pharmacokinet Biopharm 4: 255–280
Miller DR (1981) Combination use of nonsteroidal anti-inflammatory drugs. Drug Intell Clin Pharm 15: 3–7
Rothermich ND (1971) The fate of rectally administered radioactive indomethacin in human subjects: A preliminary report. Clin Pharmacol Ther 12: 300–301
Terwey-Groen CP, Heemstra S, Kraak JC (1980) Rapid determination of indomethacin and salicylic acid in serum by means of reversed-phase liquid chromatography. J Chromatogr 181: 385–397
Terhaag Von B (1979) Zur biliären Ausscheidung von Indomethazin beim Menschen. Zentralbl Pharmakol 118: 234–236
Tocco DJ, Breault GO, Zacchei AG, Steelman SL, Perrier SV (1975) Physiological disposition and metabolism of 5-(2′,4′-difluorophenyl) salicylic acid, a new salicylate. Drug Metab Dispos 3: 453–466
Upton RA, Buskin JN, Williams RL, Holford NHG, Riegelman S (1980) Negligible excretion of unchanged ketoprofen, naproxen and probenecid in urine. J Pharm Sci 69: 1254–1257
Verbeeck R, Tjandramaga TB, Mullie A, Verbesselt R, Verberckmoes R, De Schepper PJ (1979) Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency. Br J Clin Pharmacol 7: 273–282
Verbeeck R, Blackburn JL, Loewen GR (1983) Clinical pharmacokinetics of nonsteroidal anti-inflammatory drugs. Clin Pharmacokinet 8: 297–331
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Van Hecken, A., Verbesselt, R., Tjandra-Maga, T.B. et al. Pharmacokinetic interaction between indomethacin and diflunisal. Eur J Clin Pharmacol 36, 507–512 (1989). https://doi.org/10.1007/BF00558077
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DOI: https://doi.org/10.1007/BF00558077