Sulindac metabolism

Zou W, Beggs KM, Sparkenbaugh EM, et al. Sulindac metabolism and synergy with tumor necrosis factor-alpha in a drug-inflammation interaction model of idiosyncratic liver injury. / Pharmacol Exp Ther. 2009 331(1) 114-121. 

Indomethacin (Indocin) is an acetic acid derivative related functionally to sulindac (Clinoril), a prodrug with a long half-life, and etodolac (Lodine). They are metabolized in the liver and excreted as metabolites in the... 

Sulindac (Clinoril) is chemically related to indomethacin and is generally used for the same indications. It is a prodrug that is metabolized to an active sul-hde metabolite and an inactive metabolite. The most frequently reported side effects are GI pain, nausea, diarrhea, and constipation. The incidence of these effects is lower than for indomethacin, presumably because sulindac is a prodrug and thus the active metabolite is not highly concentrated at the gastric mucosa. As with indomethacin, a rather high incidence of CNS side effects (dizziness, headache) also occurs. 

Sulindac is a sulfoxide prodrug. It is reversibly metabolized to the active sulfide metabolite, which is excreted in bile and then reabsorbed from the intestine. The enterohepatic cycling prolongs the duration of action to 12-16 hours. 

Anandamide is rapidly hydrolysed enzymatically to arachidonic acid and ethanol-amine by a fatty acid amide hydrolase (FAAH) [50], The molecular characterization, cloning and expression of FAAH have been reported in a recent study [51]. FAAH can be blocked with either the general serine protease inhibitor phenyl methy(sulphonyl fluoride [38] or with the highly efficient methyl arachidonyl fluorophsphonate [52], The non-steroidal antiinflammatory ibuprofen in therapeutic doses, but not aspirin, sulindac or acetaminophen, also inhibits anandamide metabolism [53], This observation may have therapeutic implications. 

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]. 

Most functional groups bearing sulfur, other than thiols, are primarily metabolized by oxidative processes. However, sulfoxides can be reduced to sulfides. The anti-inflammatory drug sulindac is reduced to the sulfide, which is an active metabolite, and it can be oxidized back to the sulfoxide. Disulfides are reduced to the corresponding sulfides. 

While all NSAIDs have the potential for inducing renal failure, there has been speculation of quantitative differences among the individual NSAIDs. Sulindac was thought to be renal sparing, possibly because of its unusual metabolic pathway [29, 77-79]. The parent compound, sulindac sulphoxide, is an inactive prodrug, which undergoes hepatic metabolism to sulindac sulphide, the metabolite responsible for its anti-inflammatory activity. Sulindac sulphoxide is also metabolized to a much lesser extent to an inactive metabolite, sulindac sulphone. It was hypothesized that, within the human kidney, sulindac sulphide was reversibly oxidized to the inactive parent compound, sulindac sulphoxide, with the result that renal prostaglandin production was not perturbed [29, 78]. 

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, USP. Sulindac. (Z)-S-fluuru-2-meihyl-l- /t-(mcthylsuirinyl)phenyl nK thylcne -l/f-indene-.3-acctic acid (Clinoril). occurs as yellow crystals soluble in alkaline but insoluble in acidic solutions. The drug reaches peak bluod levels within 2 to 4 hours and undergoes a complicated, reversible metabolism as follows ... 

Bioprecursors do not imply a temporary linkage between the active principle and a carrier group, but result from a molecular modification of the active principle itself. This modification generates a new compound, which is a substrate for metabolizing enzymes, leading to a metabolite that is the expected active principle. This approach exemplifies the active metabolite concept in a provisional way (e.g. sulindac, fenbufen, acyclovir, losartan). 

Davis, P.J. and Guenthner, L.E. (1985) Sulindac oxidation/reduction by microbial cultures microbial models for mammalian metabolism. Xenobiotica IS 845-857,... 

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