Pharmacokinetic and pharmacodynamic implications of long-term administration of non-steroidal anti-inflammatory agents
Müller, F.O.; Hundt, H.K.; Müller, D.G.
International Journal of Clinical Pharmacology and Biopharmacy 15(9): 397-402
1977
ISSN/ISBN: 0340-0026 PMID: 914403 Document Number: 111418
Findings involving chronic administration of aspirin for 21 days to healthy volunteers in a daily dose of 60 mg/kg body wt and a study aimed at investigating a possible pharmacokinetic interaction between aspirin and diclophenac sodium are discussed. Steady state salicylic acid plasma levels were reached by day 7 in all trial subjects receiving aspirin only. These levels had decreased by 50% on day 21 in 5 out of 6 subjects. An analysis of renal elimination of salicylic acid and its main metabolites following loading doses of aspirin revealed that subjects in whom a decrease in steady state salicylic acid plasma levels occurred had a more rapid renal clearance rate of total salicylate after chronic ingestion of aspirin when compared with pretreatment values. The subject who did not exhibit a decrease of steady state salicylic acid plasma levels showed no change in his renal clearance of total salicylate. Pretreatment with diclophenac sodium (1-2 wk) appeared to enhance renal elimination of total salicylate. Concomitant oral administration of aspirin and diclophenac sodium resulted in significant acute depression of the area under curve of diclophenac serum profiles. Combination therapy with the nonsteroidal anti-inflammatory agents is possibly fraught with pharmacokinetic interaction possibilities which may have a deleterious effect upon pharmacodynamics of one or all of the agents being employed concomitantly. Chronic ingestion of aspirin gave rise to auto-induction of elimination tallies with observations of unexpectedly low steady state salicylic acid plasma levels in patients receiving doses of aspirin in the order of 60 mg/kg daily.