The metabolism and pharmacokinetics of phospho‐sulindac (OXT‐328) and the effect of difluoromethylornithine

Abstract

BACKGROUND AND PURPOSEPhospho-sulindac (PS; OXT-328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics. EXPERIMENTAL APPROACHPS metabolism was studied in cultured cells, liver microsomes and cytosol, intestinal microsomes and in mice. Pharmacokinetics and biodistribution of PS were studied in mice. KEY RESULTSPS undergoes reduction and oxidation yielding PS sulphide and PS sulphone; is hydrolysed releasing sulindac, which generates sulindac sulphide (SSide) and sulindac sulphone (SSone), all of which are glucuronidated. Liver and intestinal microsomes metabolized PS extensively but cultured cells converted only 10% of it to PS sulphide and PS sulphone. In mice, oral PS is rapidly absorbed, metabolized and distributed to the blood and other tissues. PS survives only partially intact in blood; of its three major metabolites (sulindac, SSide and SSone), sulindac has the highest Cmax and SSone the highest t1/2; their AUC0-24h are similar. Compared with conventional sulindac, PS generated more SSone but less SSide, which may contribute to the safety of PS. In the gastroduodenal wall of mice, 71% of PS was intact; sulindac, SSide and SSone together accounted for <30% of the total. This finding may explain the lack of gastrointestinal toxicity by PS. DFMO had no effect on PS metabolism but significantly reduced drug level in mouse plasma and other tissues.

Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology

“…This family of enzymes play a critical role in the inactivation of xenobiotics (14, 15). Carboxylesterases hydrolyze phospho-NSAIDs at the carboxylic ester bond, leading to the release of the native NSAID and the phospho-moiety (16, 17). Cell lines engineered to overexpress CES 1 or CES 2 actively hydrolyse phospho-NSAIDs, leading to strong resistance to their cytotoxic effects (16).…”

“…Cell lines engineered to overexpress CES 1 or CES 2 actively hydrolyse phospho-NSAIDs, leading to strong resistance to their cytotoxic effects (16). In rodents, carboxylesterase-mediated inactivation of phospho-NSAIDs occurs very rapidly, resulting in very low concentrations of the intact drug in the plasma and organs (17, 18). Importantly, there are considerable differences in the expression of carboxylesterases between humans and rodents.…”

The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism

“…The remarkable safety of PS (far superior to that of sulindac) is largely explained by its unique pharmacokinetic properties: its blood area under the curve concentration from 0 to 24 hours is around 40% of that of sulindac, and in the stomach, the organ most affected by NSAID toxicity, PS is present mainly intact with minimal levels of its harmful metabolites, sulindac and sulindac sulfide (Xie et al, 2012a). PS's more rapid detoxification by cytochrome P450s and flavin monooxygenases seems to contribute to its safety .…”

The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent

“…PS exhibited more potent anti-cancer efficacy and markedly reduced toxicity than conventional sulindac in animal models [5]. However, the carboxylester bond of PS is labile, resulting in the extensive hydrolysis of PS to sulindac in vitro and in vivo [6]. We previously demonstrated that protecting PS against its hydrolysis enhanced its anti-cancer efficacy [7].…”