Overview of phthalate ester pharmacokinetics in mammalian species

Abstract

Phthalic acid esters, or phthalate esters, are generally well absorbed from the gastrointestinal tract following oral administration. Hydrolysis to the corresponding monoester metabolite, with release of an alcoholic substituent, largely occurs prior to intestinal absorption of the longer-chain alkyl derivatives such as di(2-ethylhexyl) phthalate (DEHP). Phthalate esters are widely distributed in the body, with the liver being the major, initial repository organ. Clearance from the body is rapid and there is only a slight cumulative potential. Short-chain dialkyl phthalates, such as dimethyl phthalate, can be excreted in an unchanged form or following complete hydrolysis to phthalic acid. Longer-chain compounds such as DEHP, however, are converted principally to polar derivatives of the monoesters by oxidative metabolism prior to excretion. A marked species difference in DEHP metabolism exists: primates (man, monkey, some rodent species) glucuronidate DEHP at the carboxylate moiety following hydrolysis of a single ester linkage, whereas rats appear to be unable to glucuronidate the monoester metabolite and oxidize the residual alkyl chain instead to various ketone and carboxylate derivatives. The major route of phthalate ester elimination from the body is urinary excretion. Certain phthalate esters are excreted in the bile but undergo enterohepatic circulation. The relationships of phthalate ester pharmacokinetics to their toxicological actions are unknown at the present time, largely due to a lack of elucidated mechanisms of toxic action.