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 M, 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 M ϫ 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 M. 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 ϭ 0.016) but not with xenograft ibuprofen levels (p ϭ 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.

Pegylation Improves the Pharmacokinetics and Bioavailability of Small-Molecule Drugs Hydrolyzable by Esterases: A Study of Phospho-Ibuprofen

“…In contrast to PI-PEG and in agreement with our previous report (Xie et al, 2011), when administered intravenously, PI was almost completely hydrolyzed. Even at its maximum tolerated dose (100 mg/kg), PI exhibited low levels in the blood (AUC 0-24 hours 2.6 nmol/g  h) and was undetectable in the tumors, being rapidly hydrolyzed to release quantitatively its parent compound, ibuprofen.…”

“…The levels of PI-PEG in the circulation of mice were very high (C max . 1000 mM) in contrast to the essentially undetectable levels of PI (Xie et al, 2011). PI-PEG survived its exposure to CES, which led to high tumor drug levels, where it was present consistently and independently of its administration route.…”

“…The test compound used to demonstrate the feasibility of this approach was PI, a member of the promising phosphoNSAIDs (Xie et al, 2011). The pegylation of PI was achieved through a three-step process starting with ibuprofen.…”

“…It is of interest that in both applications the efficacy of PI against cancer was enhanced by formulating it in a nanocarrier that likely protected it from CES. Our recent PK study revealed that the bioavailability of PI in mice is low (,5%) independently of the administration route, a finding ascribed to limited aqueous solubility, hydrolysis by esterases, and rapid clearance from the systemic circulation (Xie et al, 2011).…”

Oxidative Stress Mediates through Apoptosis the Anticancer Effect of Phospho-Nonsteroidal Anti-Inflammatory Drugs: Implications for the Role of Oxidative Stress in the Action of Anticancer Agents

“…We studied four phospho-NSAIDs: P-S, P-A, P-F, and P-I Zhao et al, 2009;Mackenzie et al, 2010Mackenzie et al, , 2011Xie et al, 2011); their structures are shown in Supplemental Fig. 1.…”