Non-linearities in the pharmacokinetics of di-(2-ethylhexyl) phthalate and metabolites in male rats |
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Authors: | Per Sjöberg Ulf Bondesson Margareta Hammarlund |
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Affiliation: | (1) Department of Drugs, National Board of Health and Welfare, Box 607, 75125 Uppsala, Sweden;(2) Department of Anatomy and Histology, Faculty of Veterinary Medicine, Uppsala, Sweden;(3) Hospital Pharmacy and Psychiatric Research Centre, Ulleråker Hospital, Uppsala, Sweden;(4) Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, Uppsala, Sweden |
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Abstract: | The disposition of the plasticizer di-(2-ethylhexyl) phthalate (DEHP) and four of its major metabolites was studied in male rats given single infusions of a DEHP emulsion in doses of 5, 50 or 500 mg DEHP/kg body weight. Plasma concentrations of DEHP and metabolites were followed for 24 h after the start of the infusion. The kinetics of the primary metabolite mono-(2-ethylhexyl) phthalate (MEHP) was studied separately.The concentrations of DEHP in plasma were at all times considerably higher than those of MEHP, and the concentrations of MEHP were much higher than those of the other investigated metabolites. In animals given 500 mg DEHP/kg, the areas under the plasma concentration-time curves (AUCs) of the other investigated metabolites were at most 15% of that of MEHP. Parallel decreases in the plasma concentrations of DEHP, MEHP and the and ( -1) oxidized metabolites indicated that the elimination of DEHP was the rate-limiting step in the disposition of the metabolites. This was partly supported by the observation that the clearance of MEHP was higher than that of DEHP. Nonlinear increases in the AUCs of DEHP and MEHP indicated saturation in the formation as well as the elimination of the potentially toxic metabolite MEHP. |
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Keywords: | Diethylhexyl phthalate Monoethylhexyl phthalate Pharmacokinetics Metabolites |
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