Predictability of human pharmacokinetics of diisononyl phthalate (DINP) using chimeric mice with humanized liver

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 ra...

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Bibliographic Details
Published in:Xenobiotica 2019-11, Vol.49 (11), p.1311-1322
Main Authors: Iwata, Hiroshi, Goto, Masatomo, Sakai, Norifumi, Suemizu, Hiroshi, Yamazaki, Hiroshi
Format: Article
Language:English
Subjects:
Administration, Oral
Adult
Animals
Carbon Radioisotopes
Chimera
Dose-Response Relationship, Drug
Feces - chemistry
Female
glucuronide
Hepatocytes - transplantation
Humans
Liver - drug effects
Liver - metabolism
Male
Mice, Inbred NOD
Mice, SCID
MINP
Oxidation-Reduction
Phthalic Acids - administration & dosage
Phthalic Acids - metabolism
Phthalic Acids - pharmacokinetics
TK-NOG mice
urinary excretion
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Summary: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.
ISSN:0049-8254
1366-5928
DOI:10.1080/00498254.2018.1564087