Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 29 (12), 1903-1911

Combining Chimeric Mice With Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology

Affiliations
Review

Combining Chimeric Mice With Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology

Hiroshi Yamazaki et al. Chem Res Toxicol.

Abstract

Species differences exist in terms of drug oxidation activities, which are mediated mainly by cytochrome P450 (P450) enzymes. To overcome the problem of species extrapolation, transchromosomic mice containing a human P450 3A cluster or chimeric mice transplanted with human hepatocytes have been introduced into the human toxicology research area. In this review, drug metabolism and disposition mediated by humanized livers in chimeric mice are summarized in terms of biliary/urinary excretions of phthalate and bisphenol A and plasma clearances of the human cocktail probe drugs caffeine, warfarin, omeprazole, metoprolol, and midazolam. Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically based pharmacokinetic model based on data obtained in chimeric mice, in accordance with reported clinical thalidomide concentrations. In addition, in vivo nonspecific hepatic protein binding parameters of metabolically activated 14C-drug candidate and hepatotoxic medicines in humanized liver mice can be analyzed by accelerator mass spectrometry and are useful for predictions in humans.

Figures

Figure 1
Figure 1
Metabolic pathways of thalidomide (A) and 5-n-butyl-pyrazolo[1,5-a]pyrimidine (B). Proposed formation of the glutathione conjugate (A) is modified from Chowdhury et al.. Proposed mechanism for a putative quinone imine metabolite and conjugate formation at the 6-position (B) is taken from Kuribayashi et al.
Figure 2
Figure 2
PBPK model for animals, humanized TK-NOG mice, and humans.
Figure 3
Figure 3
Results of simplified human PBPK models for caffeine (A), S-warfarin (B), omeprazole (C), metoprolol (D), and midazolam (E) after virtual single oral doses. Solid ( formula image) and broken ( formula image), ( formula image), ( formula image), and ( formula image) lines show simplified human PBPK models based on humanized TK-NOG mouse, marmoset, cynomolgus monkey, dog, and minipig PBPK models, respectively. Circles (with SD bars) show reported mean human plasma concentrations after single oral administration of a combination of five probe drugs to 30 Caucasian subjects (2.1 mg/kg for midazolam, 10 mg for S-warfarin, 20 mg for omeprazole, and 100 mg for caffeine and metoprolol).
Figure 4
Figure 4
Plasma concentrations of thalidomide and 5-hydroxythalidomide-GSH conjugate (A) measured in control TK-NOG mice (open circles) and chimeric TK-NOG mice with humanized liver cells (solid triangles) and thalidomide (open circles, reported by Eriksson et al.; broken lines) and the sum of 5-hydroxythalidomide metabolites containing 5-hydroxythalidomide-GSH conjugate and 5,6-dihyrdoxythalidomide (solid lines) estimated in humans in silico after oral administration of a single dose of thalidomide (100 mg/kg for mice and 100 mg for humans). Results are expressed as mean values (± SD) obtained with four mice (**p < 0.01, and *p < 0.05, two-way ANOVA with Bonferroni post tests). Results are reproduced from Nishiyama et al.
Figure 5
Figure 5
Covalent binding profiles of liver microsomal protein fractions separated by two-dimensional electrophoresis. Loaded liver protein samples (100 μg) were subjected to isoelectric focusing (pI 3–10) and were then separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (10–225 kDa). In vivo liver protein bindings with metabolically activated 14C-substrates in humanized liver mice were analyzed by accelerator mass spectrometry. The results for 5-n-butyl-pyrazolo[1,5-a]pyrimidine, a new drug candidate OT-7100 metabolite, are taken from Yamazaki et al.

Similar articles

See all similar articles

Cited by 6 PubMed Central articles

See all "Cited by" articles

Publication types

Feedback