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

Abstract

Phospho-sulindac amide (PSA) is a novel potential anti-cancer and anti-inflammatory agent. Here we report the metabolism of PSA in vitro. PSA was rapidly hydroxylated at its butane-phosphate moiety to form two di-hydroxyl-PSA and four mono-hydroxyl-PSA metabolites in mouse and human liver microsomes. PSA also can be oxidized or reduced at its sulindac moiety to form PSA sulfone and PSA sulfide, respectively. PSA was mono-hydroxylated and cleared more rapidly in mouse liver microsomes than in human liver microsomes. Of eight major human cytochrome P450s (CYPs), CYP3A4 and CYP2D6 exclusively catalyzed the hydroxylation and sulfoxidation reactions of PSA, respectively. We also examined the metabolism of PSA by three major human flavin monooxygenases (FMOs). FMO1, FMO3 and FMO5 were all capable of catalyzing the sulfoxidation (but not hydroxylation) of PSA, with FMO1 being by far the most active isoform. PSA was predominantly sulfoxidized in human kidney microsomes because FMO1 is the dominant isoform in human kidney. PSA (versus sulindac) is a preferred substrate of both CYPs and FMOs, likely because of its greater lipophilicity and masked –COOH group. Ketoconazole (a CYP3A4 inhibitor) and alkaline pH strongly inhibited the hydroxylation of PSA, but moderately suppressed its sulfoxidation in liver microsomes. Together, our results establish the metabolic pathways of PSA, identify the major enzymes mediating its biotransformations and reveal significant inter-species and inter-tissue differences in its metabolism.

Genetic and Nongenetic Factors Associated with Protein Abundance of Flavin-Containing Monooxygenase 3 in Human Liver

“…Members of the FMO gene family display distinct temporal-, tissue-, and speciesspecific expression patterns (Klick and Hines, 2007). Typical FMO substrates include trimethylamine, catecholamines (Türkano glu Özçelik et al, 2013), nicotine (Bloom et al, 2013), imipramine (Wagmann et al, 2016), prothipendyl (Krueger and Williams, 2005), amitriptyline (Krueger and Williams, 2005), phospho-sulindac amide (Xie et al, 2014), benzydamine (BZD) (Taniguchi-Takizawa et al, 2015), ranitidine (Overby et al, 1997), tamoxifen (Parte and Kupfer, 2005), clozapine (Tugnait et al, 1997), diphenhydramine (Cruciani et al, 2014), and amphetamine and methamphetamine (Cashman et al, 1999).…”

NSAIDs: Old Acquaintance in the Pipeline for Cancer Treatment and Prevention─Structural Modulation, Mechanisms of Action, and Bright Future

“…This limited stability decreases their efficacy and increases their toxicity. To overcome this problem, phospho-sulindac amide (PSA, IV-7 in Figure 4) 307 and phospho-ibuprofen amide (PIA, IV-8 in Figure 4) 290 were synthesized as metabolically stable analogs of the phosphosulindac (P-S, OXT-328, IV-1 in Figure 4) and phospho- ibuprofen (MDC-917, IV-2 in Figure 4), respectively. Furthermore, phospho-ibuprofen amide (PIA) was encapsulated into liposomes to improve its pharmacokinetic profile.…”

“…In this context, several NSAID analogs mentioned previously have demonstrated potent antitumoral activity. Particularly, modifications in the NSAIDs to make them able to release antioncogenic agents such as H 2 S and NO (Figures –) − as well as phospho-NSAIDs (Figure ) − have been widely studied. Especially, HS- and HSNO-NSAIDs and phosphoramide-modified NSAIDs have been shown to improve the antitumoral activity and limit gastrointestinal side effects of NSAIDs.…”

In silico studies and in vitro microsomal metabolism of potent MetAP2 inhibitor and in vivo tumor suppressor for prostate cancer: A thioether-triazole hybrid

“…Further investigations with mouse and human liver microsomes showed that phospho-sulindac amide is oxidized or reduced. The oxidation and reduction reactions were observed with the formation of sulfone and sulfide derivatives of phospho-sulindac amide respectively (6). The metabolic pathway from sulfoxide to sulphide has been used on a common non-steroidal anti-inflammatory pro-drug, Sulindac.…”