Effect of renal failure and bis(2-ethylhexyl) phthalate pretreatment on the disposition and metabolism of antipyrine in the rat

Abstract

Renal failure patients undergoing hemodialysis are regularly exposed to phthalate plasticizers leached from dialysis tubings. Previous studies have shown that antipyrine is eliminated more rapidly in chronic renal failure patients compared with normal individuals. Therefore, the effect of bis(2-ethylhexyl) phthalate on the metabolism of antipyrine was investigated in normal and renal failure rats. In normal animals, the elimination kinetics of an intravenous dose of antipyrine (20 mg/kg) was determined before and after 14 days of peroral treatment with 2 mL/kg/d of bis(2-ethylhexyl) phthalate. The plasma clearance of antipyrine increased markedly after bis(2-ethylhexyl) phthalate treatment. There was a corresponding decrease in the elimination half-life of antipyrine, whereas the apparent volume of distribution was not affected. Both liver weight and hepatic cytochrome P450 content increased following exposure to bis(2-ethylhexyl) phthalate, indicating the induction of hepatic microsomal enzymes. The fractional urinary recovery of the N-demethyl, 4-hydroxy, and 3-hydroxymethyl metabolites of antipyrine was not altered, suggesting that all three oxidative pathways were induced to the same extent. Renal failure alone did not affect the elimination kinetics of antipyrine. However, antipyrine clearance was induced to a greater extent by bis(2-ethylhexyl) phthalate treatment in the renal failure rats as compared with the control animals. The potential for phthalate plasticizers to alter hepatic drug metabolism in hemodialysis patients should be considered.