Phospho-ibuprofen (MDC-917) is a novel agent against colon cancer: Efficacy, metabolism, and pharmacokinetics in mouse models

Gang Xie, Yu Sun, Ting Nie, Gerardo Mackenzie, Liqun Huang, Levy Kopelovich, Despina Komninou, Basil Rigas

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


We have developed a novel chemical modification of conventional nonsteroidal anti-inflammatory drugs to reduce their toxicity and enhance their efficacy. Phospho-ibuprofen [(PI) 2-(4-isobutyl-phenyl)-propionic acid-4-(diethoxy-phosphoryloxy)-butyl ester (MDC-917)], a novel derivative of ibuprofen, strongly inhibited the growth of human colon cancer cells in vitro and 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 carboxyl-PI, which can be hydrolyzed to 1-OH-ibuprofen and carboxyl-ibuprofen, respectively. PI also can be hydrolyzed to release ibuprofen, which can generate 2-OH-ibuprofen, carboxyl-ibuprofen, and ibuprofen glucuronide. After a single oral administration (400 mg/kg) of PI, ibuprofen and ibuprofen glucuronide are the main plasma metabolites of PI; they have, respectively, Cmax of 530 and 215 μM, Tmax of 1 and 2 h, elimination t1/2 of 7.7 and 5.3 h, and area under the concentration-time curve (0-24 h) of 1816 and 832 μM X h. Intact PI was detected in several tissues but not in plasma; at a higher PI dose (1200 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.

Original languageEnglish (US)
Pages (from-to)876-886
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Jun 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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