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Tytuł:
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Predictability of human pharmacokinetics of diisononyl phthalate (DINP) using chimeric mice with humanized liver.
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Autorzy:
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Iwata H; a LSI Medience Corporation , Kamisu , Japan.
Goto M; a LSI Medience Corporation , Kamisu , Japan.
Sakai N; a LSI Medience Corporation , Kamisu , Japan.
Suemizu H; b Central Institute for Experimental Animals , Kawasaki , Japan.
Yamazaki H; c Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Machida , Japan.
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Źródło:
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Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 2019 Nov; Vol. 49 (11), pp. 1311-1322. Date of Electronic Publication: 2019 Jun 21.
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Typ publikacji:
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Journal Article; Video-Audio Media
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Język:
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English
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Imprint Name(s):
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Publication: London : Informa Healthcare
Original Publication: London, Taylor & Francis.
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MeSH Terms:
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Liver/*metabolism
Phthalic Acids/*pharmacokinetics
Administration, Oral ; Adult ; Animals ; Carbon Radioisotopes ; Chimera ; Dose-Response Relationship, Drug ; Feces/chemistry ; Female ; Hepatocytes/transplantation ; Humans ; Liver/drug effects ; Male ; Mice, Inbred NOD ; Mice, SCID ; Oxidation-Reduction ; Phthalic Acids/administration & dosage ; Phthalic Acids/metabolism
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Contributed Indexing:
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Keywords: MINP; TK-NOG mice; glucuronide; liver metabolism; urinary excretion
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Substance Nomenclature:
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0 (Carbon Radioisotopes)
0 (Phthalic Acids)
0 (monoisononylphthalate)
4010KIX4CK (diisononyl phthalate)
7V68J5677O (Carbon-14)
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Entry Date(s):
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Date Created: 20181228 Date Completed: 20200205 Latest Revision: 20200205
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Update Code:
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20240105
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DOI:
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10.1080/00498254.2018.1564087
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PMID:
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30589368
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1. In order to investigate the pharmacokinetics of diisononyl phthalate (DINP) in humans, we administered [phenyl-U- 14 C]DINP at a dose of 50.0 mg/kg orally to chimeric mice (humanized-liver mice) in which the liver of TK-NOG mice (control mice) was replaced with human hepatocytes. 2. The plasma radioactivity concentrations peaked (18.0 and 59.9 µg equivalent of DINP/mL, respectively) at 2 h after administration in control and humanized-liver mice. Concentrations rose again at 8 h in controls, but not in humanized-liver mice. 3. The cumulative excretion rates in urine and feces, respectively, were 58.1% and 37.3% of the doses in controls up to 48 h, but were 86.0% and 7.7% in humanized-liver mice. 4. The main circulating metabolites in control and humanized-liver mice were monoisononyl phthalate (MINP) and the glucuronide of oxidized MINP, respectively. The urinary excretion ratio of the glucuronide of oxidized MINP in control mice was one-third of that in humanized-liver mice. 5. The present results suggested that the oxidation rates of the primary metabolite of DINP and their excretion routes to urine/feces were different for control and humanized-liver mice. Species differences in liver activities could be a determinant factor in the in vivo metabolism and disposition of diallyl phthalates such as DINP.
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