Sulindac sulfone

Sulindac shows no relevant inhibition of cyclooxygenase (Warner et al., 1999), whereas the active metabolite sulindac sulfide shows inhibition of both isoenzymes with a preference for COX-1 in a whole blood assay (see also Brideau et al., 1996 ratio COX-1/COX-2 = 0.1). Sulindac is one of the NSAIDs, extensively studied in cancer reseach (Haanen, 2001). The metabolite sulindac sulfone induces apoptosis in tumor cells. 

Sulindac is absorbed from the gastrointestinal tract and reversibly metabolised to sulindac sulfide and irreversibly metabolised to sulindac sulfone. Peak plasma... 

Structures of the metabolites sulindac sulfide and sulindac sulfone... 

Evaluation of the scavenging activity for H2O2 by NSAIDs, namely indole derivatives (indomethacin, acemetacin, etodolac), pyrrole derivatives (tol-metin, ketorolac), oxazole derivative (oxaprozin), indene derivative (sulin-dac) and its metabolites (sulindac sulfide and sulindac sulfone) was performed by Costa et al. [ 103]. The obtained results against endogenous antioxidants melatonin and GSH demonstrated that all the studied NSAIDs display... 

Fig. 5.7 Thermal scans of DPPC multil-amellar dispersions with various mole ratios of sulindac sulfide, sulindac, and sulindac sulfone (50 mM phosphate buffer, pH 7.0). (Reprinted from Fig. 6 of ref. 28 with permission from the American Chemical Society.)...

Malkinson, A.M. et al.. Inhibition of 4-(methylnitrosammo)-l-(3-pyridyl)-l-butanone-induced mouse lung tumor formation by FGN-1 (sulindac sulfone). Carcinogenesis, 19, 1353, 1998. 

Babbar N, Ignatenko NA, Casero RA Jr, Gemer EW (2003) Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. J Biol Chem 278 47762-47775... 

FIGURE 4.91 Oxidation of sulfides leads to sulfoxides followed by sulfones as shown with sulindac as an example. 

The first oxidation product of a sulfide is a sulfoxide and this can be further oxidized to a sulfone (Fig. 4.91). A good example is sulindac, which is a sulfoxide. It can be reduced to a sulfide or oxidized to a sulfone (Fig. 4.91). The sulfide is more active as a nonsteroidal anti-inflammatory agent than the parent drug but the sulfone is inactive (160). 

Sulfoxides are readily reduced to sulfides however, analogous to the oxidation aldehydes, the oxidation of sulfoxides to sulfones is irreversible as illustrated by the drug sulindac in Figure 5.13. 

FIGURE 5.13 Reduction of the sulfoxide sulindac to the sulfide is reversible, but the sulfone metabolite is not reduced back to sulindac. 

Piazza GA, Rahm AL, Krutzsch M, et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 1995 55 3110-3116. 

Sulindac is a racemic sulfoxide. Its deoxygenated metabolite (i.e., a sulfide) induces apoptosis, probably through inhibition of PPAR (Peroxisome Proliferator-Activated Receptor) It is probably the reason why suhndac seems to protect against colorectal cancers. Indeed, sulindac inhibits colorectal tumor cell growth. One other metabolite of sulindac, the sulfone exulind, is an inductor of apoptosis, and is currently in Phase III clinical trials for treatment of tumors (Figure 8.3). 

In addition to its rheumatic disease indications, sulindac suppresses familial intestinal polyposis and it may inhibit the development of colon, breast, and prostate cancer in humans. It appears to inhibit the occurrence of gastrointestinal cancer in rats. The latter effect may be caused by the sulfone rather than the sulfide. 

Sulindac has been chromatographed as the methyl ester (diazomethane) on a 6 x 10.25" 1% SE-30 on Supelcon 80/100 column under isothermal at 262°C with nitrogen as a carrier gas at 100 ml/min. Detection was with electron capture and sample sizes ranges from v50 to 100 ng. The retention time of sulindac was approximately 7 minutes. The sulfide and sulfone analogs have retention times of 1.5 and 5 mi-tion ... 

Several HPLC systems have been used for sulindac including one employing chloroform/ethyl ace-tate/acetic acid (800 200 2) as the mobile phase with a p Porasel, 30 cm, 10 u particle size column UV detection at 280 nm and a flow rate of 2.0 ml/ min (500-3000 psi). Under these conditions sulindac chromatographed with a retention time of approximately 6.3 minutes. The sulfide and sulfone analogs chromatographed with retention times of 1.8 2.5 minutes respectively 1 ). 

The major urinary metabolites are sulindac and its glucuronide, sulfone and its glucuronide and in trace amounts the insoluble sulfide metabolite and its glucuronide. The major biotransformation involves irreversible oxidation of the sulfoxide group of sulindac to sulfone and a reversible reduction to the sulfide. Studies in healthy subjects revealed that after oral administration of sulindac at least 88% is absorbed. After a single 200 mg oral dose the peak plasma concentrations of sulindac and its sulfone and sulfide metabolites were 4, 2, and 3 mg/ml respectively, and were attained after 1 hour for the parent drug and after 2 hours for each of the metabolites. 

The sulfone and its conjugates are the major products excreted in urine, and account for 27.6 + 2.8% of the administered dose. Sulindac and its glucuronide accounted for 20.2 + 0o2% of the dose excreted in the urine. Mean renal clearance of sulindac and its sulfone metabolite was 45.1 + 16.2 and 33.2 + 12.2 ml/min respectively(16). The effective half-life for accumulation is about 7 hours for sulindac(17). The long half-life is due to extensive enterohepatic recirculation(18). 

Sulindac 90 93 (and high for metabolites) 7-8 (16.4 sulfide) <1% of sulindac dose appears as active sulfide metabolite Yes sulindac and sulfone undergo extensive enterohepatic circulation relative to sulfide Extensive in liver - oxidation to sulfone, reduction to sulfide and glucuronidation Sulindac sulfide (parent is prodrug)... 

Sulindac is an inactive prodrug which needs to be converted in the liver to its active metabolite, sulindac sulfide. The metabolic pathway for sulindac is complicated, even in healthy subjects, by the reversibility of this process, the possibility of conversion to an inactive sulfone metabolite, and the extensive enterohepatic circulation of all three species [25, 26]. 

S-3)." Sulindac is administered orally, ahsorbed in the small intestine, and subsequently reduced to the active species. Administration of the inactive form has the benefit of reducing the gastrointestinal (Gl) irritation associated with the. sulfide. This example also illustrates one of the problems assrxiiated with this approach, namely, participation of alternate metabolic paths that may inactivate the compound. In this case, after absorption of. sulindac. irreversible metabolic oxidation of the sulfoxide to the sulfone can also occur to give an inactive compound. 

Sulindac is oxidized to the sulfone and then reversibly reduced to the active sulfide by the action of bowel microflora on sulindac excreted in the bile. 

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