Human urinary concentrations of monoisononyl phthalate estimated using physiologically based pharmacokinetic modeling and experimental pharmacokinetics in humanized-liver mice orally administered with diisononyl phthalate
| Autor: | Masatomo Goto, Hiroshi Suemizu, Tomonori Miura, Hiroshi Iwata, Makiko Shimizu, Hiroshi Yamazaki, Norifumi Sakai |
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| Rok vydání: | 2018 |
| Předmět: |
Physiologically based pharmacokinetic modelling
Health Toxicology and Mutagenesis Phthalic Acids Urine Toxicology Models Biological 030226 pharmacology & pharmacy Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Animals Humans Ingestion Pharmacology Diisononyl phthalate Chromatography Phthalate General Medicine Phthalic acid Liver chemistry 030220 oncology & carcinogenesis Glucuronide |
| Zdroj: | Xenobiotica. 49:513-520 |
| ISSN: | 1366-5928 0049-8254 |
| DOI: | 10.1080/00498254.2018.1471753 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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