ARE ALTERED PHARMACOKINETICS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) A RISK FACTOR FOR GASTROINTESTINAL-BLEEDING

Aims We hypothesised that pharmacokinetic factors might go some way to explaining the risk of major gastrointestinal haemorrhage with non-st eroidal antiinflammatory drugs (NSAIDs), with bleeders exhibiting a re duced clearance of NSAIDs compared with non-bleeders and set out to in vestigate this. Methods Fifty patients presenting to hospital with acu te gastrointestinal bleeding while taking piroxicam, indomethacin, dic lofenac or naproxen and age, sex, musculoskeletal disease and drug mat ched community dwelling controls, up to two for each index case, who h ad not bled were recruited. Clinical details including duration of the rapy were recorded. Bleeders discontinued the implicated NSAID at pres entation, controls at least five half-lives before the study. Bleeders were contacted by letter 1 month after discharge and invited to take part and were studied after a median delay of 5 months. Subjects recei ved an oral dose of their respective NSAID and venous blood was sample d, over a period determined by the half-life of the NSAID. Plasma conc entrations were determined by high performance liquid chromatography. Results The median length of treatment for the index patients was 1 ye ar (range 2 weeks--28 years) and for the control patients 2 years (1 m onth--25 years), P<0.0005. There were no significant differences in pe ak plasma concentration, time to peak plasma concentration or area und er the plasma concentration-time curve between bleeders or controls fo r any of the NSAIDs studied, apart from piroxicam C-max being lower in bleeders at 2.07 mg l(-1) than in controls at 3.21 mg l(-1), mean dif ference (95% CI) -- 1.14 (-1.83--0.48), P<0.005. Conclusions The data failed to support the hypothesis that reduced clearance of NSAIDs, whi ch results in higher plasma concentrations, is a risk factor for acute gastrointestinal haemorrhage.