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

Abstract

1. In order to investigate the pharmacokinetics of diisononyl phthalate (DINP) in humans, we administered [phenyl-U-14C]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.