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, 49 (5), 513-520

Human Urinary Concentrations of Monoisononyl Phthalate Estimated Using Physiologically Based Pharmacokinetic Modeling and Experimental Pharmacokinetics in Humanized-Liver Mice Orally Administered With Diisononyl Phthalate

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Human Urinary Concentrations of Monoisononyl Phthalate Estimated Using Physiologically Based Pharmacokinetic Modeling and Experimental Pharmacokinetics in Humanized-Liver Mice Orally Administered With Diisononyl Phthalate

Tomonori Miura et al. Xenobiotica.

Abstract

Diisononyl phthalate (DINP) used as a plasticizer is a mixture of compounds consisting of isononyl esters of phthalic acid. There are concerns about the bioaccumulation of such esters in humans. A [phenyl-U-14C]DINP mixture was synthesized and orally administered (50 mg/kg body weight) to control and humanized-liver mice and their pharmacokinetics were determined. Monoisononyl phthalate (MINP, a primary metabolite of DINP), oxidized MINP (isomers with hydroxy, carbonyl, and carboxy functional groups), and their glucuronides were detected in plasma from control and humanized-liver mice. Biphasic plasma concentration-time curves of MINP and its glucuronide were seen in control mice. In contrast, no such biphasic relationship was seen in humanized-liver mice, in which MINP and oxidized MINP were extensively excreted in the urine within 48 h. Animal biomonitoring equivalents of MINP and oxidized MINP from humanized-liver mice studies were scaled to human equivalents using known species allometric scaling factors with a simple physiologically based pharmacokinetic (PBPK) model. Estimated urinary oxidized MINP concentrations in humans were roughly consistent with reported concentrations of MINP (with a different side chain). The simplified PBPK model could estimate human urinary concentrations of MINP after ingestion of DINP and was capable of both forward and reverse dosimetry.

Keywords: Allometric scaling; kinetic modeling; phthalate; species difference; urine.

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