Are altered pharmacokinetics of non‐steroidal anti‐inflammatory drugs (NSAIDs) a risk factor for gastrointestinal bleeding?

Abstract

AimsWe hypothesised that pharmacokinetic factors might go some way to explaining the risk of major gastrointestinal haemorrhage with non-steroidal antiinflammatory drugs (NSAIDs), with bleeders exhibiting a reduced clearance of NSAIDs compared with non-bleeders and set out to investigate this. Methods Fifty patients presenting to hospital with acute gastrointestinal bleeding while taking piroxicam, indomethacin, diclofenac or naproxen and age, sex, musculoskeletal disease and drug matched community dwelling controls, up to two for each index case, who had not bled were recruited. Clinical details including duration of therapy were recorded. Bleeders discontinued the implicated NSAID at presentation, 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 received an oral dose of their respective NSAID and venous blood was sampled, over a period determined by the half-life of the NSAID. Plasma concentrations were determined by high performance liquid chromatography. Results The median length of treatment for the index patients was 1 year (range 2 weeks-28 years) and for the control patients 2 years (1 month-25 years), P<0.0005. There were no significant differences in peak plasma concentration, time to peak plasma concentration or area under the plasma concentration-time curve between bleeders or controls for 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 difference (95% CI) −1.14 (−1.83-−0.48), P<0.005. Conclusions The data failed to support the hypothesis that reduced clearance of NSAIDs, which results in higher plasma concentrations, is a risk factor for acute gastrointestinal haemorrhage.

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…A third study investigated the pharmacokinetics of piroxicam, indomethacin, diclofenac, and naproxen in patients with and without a history of GI bleeding with these drugs. A trend was observed for lower rather than higher AUCs among those who bled, which does not support a relationship with CYP2C9 polymorphism (Wynne et al, 1998). Thus, overall the evidence for a gene-effect relationship is weak at present.…”

Pharmacogenetics of nonsteroidal anti-inflammatory drugs

“…40 Furthermore, there was no significant difference between the C max and AUC for naproxen in patients experiencing gastrointestinal bleeding compared with those without bleeding from two studies. 41,42 The subsequent frequency of CYP2C9 genotype was comparable to that of subjects with a history of gastric ulcers associated with NSAID use and those receiving NSAIDs minus the gastric ulceration. 41,42 ENOLIC ACIDS Enolic acids inhibit COX-1 and COX-2 while also possessing antiinflammatory and analgesic action.…”

“…41,42 The subsequent frequency of CYP2C9 genotype was comparable to that of subjects with a history of gastric ulcers associated with NSAID use and those receiving NSAIDs minus the gastric ulceration. 41,42 ENOLIC ACIDS Enolic acids inhibit COX-1 and COX-2 while also possessing antiinflammatory and analgesic action. The enolic acids hold efficacy that is similar to aspirin, indomethacin or naproxen for two specific disease states, rheumatoid arthritis and osteoarthritis.…”

“…40 There was no significant difference in the AUC for indomethacin in patients experiencing gastrointestinal bleeding compared with those without bleeding. 41 An additional study assessed the frequency of the CYP2C9 variation among 20 þ individuals with a past medical history of NSAIDrelated gastric ulceration versus 30 þ individuals who did not have a history of gastropathy. 42 The ensuing frequency of CYP2C9*1/*1 (wild-type) genotype was similar to that possessed by subjects with a history of gastric ulcers associated with NSAID use and those receiving NSAIDs without the gastric ulceration.…”

IMPACT OFCYP2C9GENOTYPE ON PHARMACOKINETICS: ARE ALL CYCLOOXYGENASE INHIBITORS THE SAME?: TABLE 1

“…For example, Wynne et al (1998) hypothesized that PK might explain the risk of major GI hemorrhage with NSAIDs, with bleeders exhibiting a reduced clearance of NSAIDs compared with nonbleeders. A number of patients (n ϭ 50), hospitalized with GI bleeds while taking piroxicam, indomethacin, diclofenac, or naproxen, were evaluated.…”