title: Influence of chronic diflunisal treatment on the plasma levels, metabolism and excretion of indomethacin.
abstract: The single-dose pharmacokinetics of indomethacin following 100 mg rectally was measured in two groups of 8 healthy subjects before and after diflunisal 500 mg p.o. once daily, or 500 mg in the morning and 1000 mg in the evening, until steady state conditions were reached. A further group of 8 healthy subjects was given 50 mg indomethacin rectally before and after diflunisal 500 mg p.o. twice daily. High dose diflunisal (1500 mg/day) decreased the renal clearance of indomethacin from 21.9 to 1.8 ml/min (92%) and reduced the renal excretion of both unchanged (63%) and conjugated (82%) indomethacin. The apparent total body clearance (0.12 l/h/kg), apparent volume of distribution (0.98 l/kg), and volume of distribution at steady state (0.80 l/kg) were decreased by 47%, 35% and 30%. The maximum plasma concentration (2.4 micrograms/ml) and total area under the curve (13.0 micrograms x h/ml) were increased by 40% and 119%, respectively. The terminal elimination half-life (5.7 h) and mean residence time (6.7 h) were slightly prolonged (7.0 h and 8.8 h) in the presence of diflunisal. The contribution of metabolism to the overall elimination of indomethacin was increased by only 2%. Similar results were obtained when the subjects were challenged with the low dose of diflunisal (500 mg/day), although the magnitude of the changes were smaller. The interaction between indomethacin and diflunisal may be due to competition both at the metabolic (conjugation) and the excretory (tubular secretion) levels.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Clinical Pharmacology, University of Lund, Sweden.
authors.forename: L O
authors.initials: LO
authors.lastname: Eriksson
authors.forename: E
authors.initials: E
authors.lastname: Wåhlin-Boll
authors.forename: H
authors.initials: H
authors.lastname: Liedholm
authors.forename: P
authors.initials: P
authors.lastname: Seideman
authors.forename: A
authors.initials: A
authors.lastname: Melander
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D004061:Diflunisal / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007213:Indomethacin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced
chemical_list: D004061:Diflunisal; D007213:Indomethacin