We have recently developed a novel chemical modification of conventional NSAIDs in order to reduce their toxicity and enhance their efficacy. Phospho-ibuprofen (PI; MDC-917), a novel derivative of ibuprofen strongly inhibited the growth of human colon cancer cells in vitro and of SW480 human colon cancer xenografts in nude mice. PI was metabolized minimally by cultured cells, but extensively by liver microsomes and mice, undergoing regioselective oxidation to produce 1-OH-PI and carboxy-PI, which can be hydrolyzed to 1-OH-ibuprofen and carboxy-ibuprofen, respectively. PI also can be hydrolyzed to release ibuprofen, which can generate 2-OH-ibuprofen, carboxy-ibuprofen and ibuprofen glucuronide. Following a single oral administration of PI 400 mg/kg, ibuprofen and ibuprofen glucuronide are the main plasma metabolites of PI; they have, respectively, Cmax 530 and 215 μM, Tmax 1 and 2 h, elimination t1/2 7.7 and 5.3 h, and AUC0-24h 1,816 and 832 μM*h. Intact PI was detected in several tissues but not in plasma; at a higher PI dose (1,200 mg/kg), PI plasma levels were 12.4 μM. PI generated the same metabolites in mouse plasma as conventional ibuprofen, but with much lower levels, perhaps accounting for the enhanced safety of PI. The antitumor effect of PI was significantly associated with plasma ibuprofen levels (p=0.016) but not with xenograft ibuprofen levels (p=0.08), suggesting a complex anticancer effect. These results provide a pharmacological basis to explain, at least in part, the anticancer efficacy and safety of this promising compound, and indicate that PI merits further evaluation as an anticancer agent.
- Received January 31, 2011.
- Revision received March 8, 2011.
- Accepted March 8, 2011.
- The American Society for Pharmacology and Experimental Therapeutics