Abstract

Numerous studies in humans have demonstrated increases in intestinal permeability resulting from the administration of non-steroidal anti-inflammatory drugs (NSAIDs). The increased permeability correlates well with ulceration. The time course of the changes in intestinal permeability, however, has not been studied, which makes comparative studies between different NSAIDs or different formulations of the same drug difficult. In the present study we have administered single doses of indomethacin to examine both the time course and pharmacokinetic/pharmacodynamic relationships of intestinal permeability in rats estimated by following the urinary excretion of [⁵¹Cr]-EDTA. The change in intestinal permeability was both time- and dose-dependent. Following both 10 mg kg⁻¹and 20 mg kg⁻¹oral doses of indomethacin, there was a rapid rise in intestinal permeability to a maximum level, after at least 12 h post-dose, which is longer than those previously observed for ibuprofen, ketoprofen, flurbiprofen and naproxen. The maximal effect lasted 12 and 36 h following 10 and 20 mg kg⁻¹doses, respectively. The side-effect–plasma concentration relationship demonstrated a counter-clockwise hysteresis. The relationship between the observed side-effect and the estimated deep effect compartment concentration was, on the other hand, linear. In comparative permeability studies of NSAIDs the time of administration, concentration and drug dependencies should be considered.

Author Keywords: indomethacin; non-steroidal anti-inflammatory drug; pharmacokinetics; pharmacodynamics

^f1 Present addresses: Dupont-Merck Pharmaceutical Company, Drug Metabloism and Pharmacokinetics; Stine-Haskell Research Center, Newark, Delaware, USA and

^f2 Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.

^f3 Corresponding author. F. Jamali, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. T6G 2N8.