Effect of subacute ibuprofen dosing on rectal mucosal prostaglandin E₂ levels in healthy subjects with a history of resected polyps

Nonsteroidal antiinflammatory drugs are among the most promising chemopreventive agents for colorectal cancer. Although the mechanism by which nonsteroidal antiinflammatory drugs exert such effects remains to be further characterized, their best known pharmacological effect is inhibition of prostaglandin synthetase, which leads to decreases in tissue prostaglandin levels. We conducted a randomized, double-blind, controlled study to examine the effect of daily ibuprofen treatment on the rectal mucosal prostaglandin E₂ (PGE₂) levels in healthy subjects with a history of resected polyps. Study participants (n = 27) completed a 2-week run-in period and were then randomized to take a single, daily dose of ibuprofen (300 or 600 mg) or of a placebo for 4 weeks. Rectal biopsy specimens were taken before and after the run-in period and at 2 and 4 weeks after the ibuprofen/placebo treatment. Notably large between- and within-subject variability in the rectal mucosal PGE₂ content was seen. The changes in PGE₂ levels after ibuprofen/placebo treatment correlated with the baseline PGE₂ content. After adjustment of the baseline values, 2 weeks of 300 mg/day of ibuprofen treatment resulted in significantly more suppression of PGE₂ levels than that observed after the placebo treatment (55% versus 22% suppression from baseline; P = 0.033). Although other ibuprofen treatment schedules and doses appeared to result in suppression in the PGE₂ levels, the suppression was not statistically significant because of the large variability in this measurement. Because lower doses are associated with fewer adverse effects, a dose of 300 mg of ibuprofen/day should be considered for future Phase II chemoprevention studies. Stratifying study participants, based on their baseline PGE₂ levels and inclusion of a larger number of study subjects, are recommended for future trials where the rectal mucosal PGE₂ level is to be used as a surrogate end point biomarker.