Sulindac

Sulindac is a prodrug. Sulindac metabolizes to sulindac sulfide, a cyclooxgenase inhibitor that represses ras signaling, and sulindac sulfone, an antitumor agent, following oral administration in vivo.

Effect of Sulindac Binary System on In Vitro and In Vivo Release Profiles: An Assessment of Polymer Type and Its Ratio.[Pubmed:27840824]

Biomed Res Int. 2016;2016:3182358.

The bioavailability of Sulindac (SDC), a nonsteroidal anti-inflammatory drug, is low due to poor aqueous solubility and poor dissolution rate. For this reason it is necessary to enhance the solubility and enhance dissolution of the drug by dispersing SDC in polyethylene glycols 6000 (PEG 6000) and polyvinyl pyrrolidone 40000 (PVP 40000) matrices using the coevaporation technique. Studying the influence of SDC to polymer ratio on drug content, percent yield, particle size, and in vitro release was performed. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy were used to characterize any change in crystal habit of SDC in the prepared formulae. The anti-inflammatory effect of SDC was studied using the hind paw edema model. It was found that incorporation of SDC in PEG 6000 and PVP 40000 matrices resulted in improving the dissolution rate, which was found to depend on the polymer and its weight ratio of the drug. It is clearly obvious that the dissolution rate was remarkably improved in drug PVP 40000 molecular dispersions when compared to drug PEG 6000 systems. Solid dispersion of SDC in PEG and PVP improved the anti-inflammatory effect of SDC and it was found that formula SDV5 exhibited a more pronounced inhibition of swelling than other formulae.

Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers.[Pubmed:28331852]

Biomed Res Int. 2017;2017:4189678.

Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of Sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of Sulindac, Sulindac sulfide, and Sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D' = 0.977, r(2) = 0.944). The mean values of Cmax, AUC0-24, and AUC0-infinity of Sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P < 0.05), while the pharmacokinetic parameters except Tmax of Sulindac sulfide and Sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of Sulindac in Chinese healthy male volunteers.

Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion.[Pubmed:28276667]

J Biomed Res. 2016 Mar;30(2):120-133.

ATP-binding cassette (ABC) transporters ABCC1 (MRP1), ABCB1 (P-gp), and ABCG2 (BCRP) contribute to chemotherapy failure. The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug (NSAID), Sulindac sulfide, to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if Sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux. Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs. NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines, as well as a large panel of standard tumor cell lines. Other experiments characterized the mechanism by which Sulindac sulfide inhibits ABCC1 substrate and co-substrate (GSH) transport in isolated membrane vesicles and intact cells. Selective reversal of multi-drug resistance (MDR), decreased efflux of doxorubicin, and fluorescent substrates were demonstrated by Sulindac sulfide and a related NSAID, indomethacin, in resistance selected and engineered cell lines expressing ABCC1, but not ABCB1 or ABCG2. Sulindac sulfide also inhibited transport of leukotriene C4 into membrane vesicles. Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines, including all melanoma lines tested (7-7). Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells, while the glutathione synthesis inhibitor, BSO, selectively increased sensitivity to Sulindac sulfide induced cytotoxicity. Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations. ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of Sulindac sulfide, and in combination with chemotherapeutic drugs that induce oxidative stress.

Marmoset Flavin-Containing Monooxygenase 3 in the Liver Is a Major Benzydamine and Sulindac Sulfide Oxygenase.[Pubmed:28258069]

Drug Metab Dispos. 2017 May;45(5):497-500.

Common marmosets (Callithrix jacchus) are potentially primate models for preclinical drug metabolism studies because there are similarities in the molecular characteristics of cytochrome P450 enzymes between this species and humans. However, characterization of non-cytochrome P450 enzymes has not been clarified in marmosets. Here, we report characterization of flavin-containing monooxygenases FMO1-FMO5 identified in marmoset tissues. Marmoset FMO forms shared high amino acid sequence identities (93%-95%) and phylogenetic closeness with human homologous FMO forms. FMO1 and FMO3 mRNA were abundantly expressed in the liver and kidneys among five marmoset tissues examined, where FMO3 protein was detected by immunoblotting. FMO inhibition assays using preheated tissue microsomes indicated that benzydamine N-oxygenation and Sulindac sulfide S-oxygenation in the marmoset liver was mainly catalyzed by FMO3, the major hepatic FMO. Marmoset FMO3 protein heterologously expressed in Escherichia coli effectively catalyzed benzydamine N-oxygenation and Sulindac sulfide S-oxygenation comparable to marmoset liver microsomes. These results indicate that the FMO3 enzyme expressed in marmoset livers mainly metabolizes benzydamine and Sulindac sulfide (typical human FMO substrates), suggesting its importance for FMO-dependent drug metabolism in marmosets.

Sulindac and its derivatives: a novel class of anticancer agents.[Pubmed:11569947]

Curr Opin Investig Drugs. 2001 May;2(5):677-83.

It has been repeatedly observed that non-steroidal anti-inflammatory drugs, in particular Sulindac and derivatives, may effectively prevent colorectal cancer. It has become apparent that exisulind (Sulindac sulfone) induces apoptosis in tumor cells. Cell biological studies provided circumstantial evidence that the mechanism by which these agents exert their antitumor effect should be attributed to inhibition of cyclic-GMP phosphodiesterase (cGMP-PDE). The secondary increase of cGMP activates protein kinase G (PKG) and induces transcription of caspase genes, resulting in apoptosis. cGMP-PDEs comprise 11 gene families. Each family of PDEs is characterized by their ability to bind and degrade cAMP and cGMP but differs in physical and kinetic properties. Any single type of cell expresses a limited number of PDE-isoforms in order to regulate cGMP or cAMP levels. The majority of PDE inhibitors that have been investigated until now, except exisulind and a number of its analogs, do not induce apoptosis in tumor cells. Sulindac has a preventive effect on tumorigenesis in patients with polyposis of the colon. The anticancer effect of the novel Sulindac derivatives has been demonstrated in over 50 different tumor cell lines, as well as in animal models of a variety of human cancers, such as mammary, prostate, lung and pancreatic carcinomas. Selective apoptotic antineoplastic drugs (SAANDs), as developed by Cell Pathways Inc, represent a novel class of anticancer agents that target a novel form of cGMP-PDE. It is believed that this enzyme is selectively increased in precancerous and cancerous cells. By specifically inhibiting the action of this particular cGMP-PDE, SAANDs enable various tumor cells to process an apoptotic signal and to commit suicide without affecting normal cells. As a result, side effects normally associated with traditional chemotherapeutic agents are not observed. One of the new compounds, CP-461, appeared < or = 100-fold more potent than exisulind in vitro. Studies of human cancer cell lines in vitro and dose-ranging phase I/II studies, both oral and iv, are discussed. Combinations of CP-461 with other chemotherapeutic agents are well tolerated.

Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells.[Pubmed:11118042]

Cancer Res. 2000 Dec 1;60(23):6607-10.

Both the sulfide and sulfone metabolites of Sulindac, a nonsteroidal anti-inflammatory drug, display anticarcinogenic effects in experimental models. Sulindac sulfide inhibits cyclooxygenase (COX) enzyme activities and has been reported to suppress ras-dependent signaling. However, the mechanisms by which Sulindac sulfone suppresses cancer growth are not as defined. We studied the effects of these Sulindac metabolites in human colon cancer-derived Caco-2 cells that have been transfected with an activated K-ras oncogene. Stable transfected clones expressed high levels of COX-2 mRNA and protein, compared with parental cells. K-ras-transfected cells formed tumors more quickly when injected into severe combined immunodeficiency disease mice than parental cells, and this tumorigenesis was suppressed by treatment with Sulindac. Sulindac sulfone inhibited COX-2 protein expression, which resulted in a decrease in prostaglandin synthase E2 production. Sulindac sulfide had little effect on COX-2 in this model, but did suppress prostaglandin synthase E2 production, presumably by inhibiting COX enzyme activity. These data indicate that the sulfide and sulfone derivatives of Sulindac exert COX-dependent effects by distinct mechanisms.