Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to prevent early neoplastic progression and malignant conversion. The use of NSAIDs in preventing colon cancer has been limited because of significant toxicities associated with long-term use. Xie et al. characterized the pharmacokinetics, metabolism, and pharmacodynamics of phosphoibuprofen (MDC-917), aimed at reducing its toxicity and enhancing its efficacy against colon cancer. MDC-917 was shown to be 16 to 23 times more potent than ibuprofen in cultured colon cancer cells and was also efficacious in xenograft models of colon cancer. MDC-917 was minimally metabolized by cultured cells to ibuprofen, which is 22-fold less potent in inhibiting cancer cell growth. MDC-917 is extensively metabolized by microsomes and in mice, undergoing regioselective oxidation. Ibuprofen and ibuprofen glucuronide are the primary metabolites after oral administration of MDC-917 and produced the same metabolic profile as ibuprofen in vivo. Antitumor effects were associated with plasma ibuprofen levels but not ibuprofen levels in the tumor. It is noteworthy that MDC-917 generated lower AUC0-24h and fewer total metabolites compared with ibuprofen when administered on an equimolar basis; it is conceivable that these differences account, at least partially, for the greater safety of MDC-917 compared with ibuprofen.
See article at J Pharmacol Exp Ther 2011, 337:876–886
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