Inhibition of sulindac metabolism by dimethyl sulfoxide in the rat.
Dimethyl sulfoxide (DMSO) suppresses conversion of the prodrug sulindac to its bioactive sulfide metabolite (SD) by competitively inhibiting sulfoxide reductase. During continuous iv infusions of sulindac (1 mg/kg X h), plasma concentrations of SD at steady-state equilibrium were 80% lower when DMSO was infused concomitantly at 0.34 ml/kg X h, whereas sulindac plasma concentrations were not significantly affected by DMSO. Dermal application and intragastric administration of DMSO also inhibited SD accumulation in plasma. DMSO was only a weak inhibitor of SD oxidation in vitro and did not affect the rate of SD elimination in vivo. In contrast, dimethyl sulfide, a metabolite of DMSO, was a potent inhibitor of SD oxidase in vitro. These data suggest that DMSO can inhibit bioactivation and, hence, the antiinflammatory effects of sulindac.
D000284:Administration, Oral; D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004347:Drug Interactions; D066298:In Vitro Techniques; D007192:Indenes / Q000378:metabolism*; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D012869:Skin Absorption; D013467:Sulindac / Q000097:blood / Q000378:metabolism*
D007192:Indenes; D013467:Sulindac; D004121:Dimethyl Sulfoxide