title: Phospho-ibuprofen (MDC-917) is a novel agent against colon cancer: efficacy, metabolism, and pharmacokinetics in mouse models.
abstract: 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, C(max) of 530 and 215 μM, T(max) of 1 and 2 h, elimination t(1/2) of 7.7 and 5.3 h, and area under the concentration-time curve (0-24 h) of 1816 and 832 μM × 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.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794-8173, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Xie
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Ting
authors.initials: T
authors.lastname: Nie
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.forename: Liqun
authors.initials: L
authors.lastname: Huang
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Despina
authors.initials: D
authors.lastname: Komninou
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D010755:Organophosphates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C559491:2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester; D000970:Antineoplastic Agents; D010755:Organophosphates; D004950:Esterases; D007052:Ibuprofen