Metabolic inhibition and di-2-ethylhexyl phthalate pharmacokinetics in fish

A pharmacokinetic model for the accumulation of di-2-ethylhexyl phthalate (DEHP) by sheepshead minnow predicted a significant increase in the bioconcentration factor (BCF) of DEHP if its metabolism were inhibited. To test this prediction, fish were treated with either piperonyl butoxide (PBO) or bis-(p-nitrophenyl)phosphate (BNPP) before and during their exposure to DEHP. Compared with the controls, the PBO-treated fish showed no significant differences in either the amount of total metabolites in the fish and exposure water or the amount of DEHP in the fish. Conversely, the total amount of metabolites formed by BNPP-treated fish was only 23% of that in the control. This indicated that hydrolysis was a major pathway for DEHP metabolism in sheepshead minnow. The amount of DEHP accumulated by the BNPP-treated fish was almost twice that of the controls, which also agreed with the model prediction. A pharmacokinetic analysis of the time course of DEHP accumulation and metabolism indicated that BNPP altered the dynamics of DEHP in the fish beyond simply reducing the metabolic clearance. BNPP reduced the value of the absorption clearance to half that of the control, and the phthalate appeared to distribute more rapidly to the poorly perfused tissues. These effects may have been caused by the anticholinesterase activity of BNPP. The model-predicted BCF of DEHP in BNPP-treated fish was more than 6 times the control value, apparently as a consequence of decreased metabolic clearance and increased volume of distribution.