Subacute arsenic exposure through drinking water reduces the pharmacodynamic effects of ketoprofen in male rats

Abstract

We evaluated the modulatory role of the groundwater contaminant arsenic on the pharmacodynamic responses of the nonsteroidal analgesic–antipyretic drug ketoprofen and the major pro-inflammatory mediators linked to the mechanism of ketoprofen's therapeutic effects. Rats were pre-exposed to sodium arsenite (0.4, 4 and 40ppm) through drinking water for 28 days. The pharmacological effects of orally administered ketoprofen (5mg/kg) were evaluated the following day. Pain, inflammation and pyretic responses were, respectively, assessed through formalin-induced nociception, carrageenan-induced inflammation and lipopolysaccharide-induced pyrexia. Arsenic inhibited ketoprofen's analgesic, anti-inflammatory and antipyretic effects. Further, arsenic enhanced cyclooxygenase-1 and cyclooxygenase-2 activities and tumor necrosis factor-α, interleukin-1β and prostaglandin-E2 production in hind paw muscle. These results suggest a functional antagonism of ketoprofen by arsenic. This may relate to arsenic-mediated local release of tumor necrosis factor-α and interleukin-1β, which causes cyclooxygenase induction and consequent prostaglandin-E2 release. In conclusion, subacute exposure to environmentally relevant concentrations of arsenic through drinking water may aggravate pain, inflammation and pyrexia and thereby, may reduce the therapeutic efficacy of ketoprofen.