Chimeric Mice with Humanized Livers: A Unique Tool for  in Vivo and in Vitro Enzyme Induction Studies

Kakuni, Masakazu; Yamasaki, Chihiro; Tachibana, Asato; Yoshizane, Yasumi; Ishida, Yuji; Tateno, Chise

doi:10.3390/ijms15010058

Cited by 42 publications

(37 citation statements)

References 24 publications

(30 reference statements)

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“…The observed results for plasma concentrations of RIF are in agreement with that of data reported. 16,28 The AUC and the C max values in the lung homogenates were about half of that in the plasma. The T max (120 min) observed in the brain homogenate was twice that observed in both the plasma and lung matrices, respectively.…”

Section: Resultsmentioning

confidence: 98%

Visualization of Time-Dependent Distribution of Rifampicin in Rat Brain Using MALDI MSI and Quantitative LCMS/MS

Shobo

BratkowskaDominika

Baijnath

et al. 2015

ASSAY and Drug Development Technologies

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Rifampicin (RIF) is a major component for short-course chemotherapy against tuberculosis, since it is active against rapidly metabolizing as well as dormant bacteria. According to the Lipinski rules, RIF should not enter the blood-brain barrier. Visualization of tissue drug distribution is of major importance in pharmacological studies; thus, far imaging of RIF in the brain has been limited to positron emission tomography. We propose using matrix-assisted laser desorption/ionization mass spectrometry imaging techniques as a suitable alternative for the visualization and localization of drug tissue distribution. Using the liquid chromatography mass spectrometric (LCMS) technique, we were able to quantify the concentrations of RIF in the uninfected rat brain; we paired this with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to show the time-dependent manner in which RIF is able to enter the brain. Our results show that even at the minute concentrations measured with LCMS/MS we were able visualize the drug and show its exact distribution in the rat brain. Other available methods require nuclear labeling and the detection of gamma rays produced by labeled compounds to visualize the compound and its localization; MALDI MSI is a more recently developed technique, which can provide detailed information on drug distribution in tissues when compared to other imaging techniques. This study shows that without any requirement for complex preprocessing we are able to produce images with a relatively improved resolution and localization than those acquired using more complex imaging methods, showing MALDI MSI to be an invaluable tool in drug distribution studies.

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Section: Resultsmentioning

confidence: 98%

Visualization of Time-Dependent Distribution of Rifampicin in Rat Brain Using MALDI MSI and Quantitative LCMS/MS

Shobo

BratkowskaDominika

Baijnath

et al. 2015

ASSAY and Drug Development Technologies

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“…To evaluate the specificity, we treated normal human hepatocytes, PXB cells isolated from chimeric mice with a humanized liver (PXB mice)12, with the HDACis, and found no or little alteration in the MICA mRNA expression level and cytotoxicity by treatment with VOR (Fig. 4M,N), BEL, ENT, MOC, or RES (Fig.…”

Section: Resultsmentioning

confidence: 99%

Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study

Goto

Annan

Morita

et al. 2016

Sci Rep

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Pharmacotherapeutic options are limited for hepatocellular carcinoma (HCC). Recently, we identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) gene as a susceptibility gene for hepatitis C virus-induced HCC in a genome-wide association study (GWAS). To prove the concept of HCC immunotherapy based on the results of a GWAS, in the present study, we searched for drugs that could restore MICA expression. A screen of the FDA-approved drug library identified the anti-cancer agent vorinostat as the strongest hit, suggesting histone deacetylase inhibitors (HDACis) as potent candidates. Indeed, the HDACi-induced expression of MICA specific to HCC cells enhanced natural killer (NK) cell-mediated cytotoxicity in co-culture, which was further reinforced by treatment with an inhibitor of MICA sheddase. Similarly augmented anti-tumor activity of NK cells via NK group 2D was observed in vivo. Metabolomics analysis revealed HDACi-mediated alterations in energy supply and stresses for MICA induction and HCC inhibition, providing a mechanism for the chemoimmunotherapeutic actions. These data are indicative of promising strategies for selective HCC innate immunotherapy.

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“…PXB mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes (Tateno et al, 2004(Tateno et al, , 2015. The expression levels (both mRNA and protein) of metabolic enzymes and transporters in human hepatocytes of PXB mice were previously reported to be similar to those in humans (Tateno et al, 2004;Nishimura et al, 2005;Okumura et al, 2007;Ohtsuki et al, 2014), and PXB mice have been characterized in detail and widely used in drug discovery to predict human-specific metabolite identification (Samuelsson et al, 2012;Bateman et al, 2014), induction and inhibition of drug metabolic enzymes (Katoh et al, 2005;Katoh and Yokoi, 2007;Hasegawa et al, 2012;Kakuni et al, 2013), human pharmacokinetics (Sanoh et al, 2012(Sanoh et al, , 2015Miyamoto et al, 2017), and secretion into bile (Okumura et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Organic Anion–Transporting Polypeptide (OATP)–Mediated Drug-Drug Interaction Study between Rosuvastatin and Cyclosporine A in Chimeric Mice with Humanized Liver

et al. 2017

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The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and DDIs via transporters may be a risk factor for adverse events. Cyclosporine A, a strong OATP inhibitor, has been reported to increase the systemic exposure of rosuvastatin, an OATP substrate, by 7.1-fold in clinical studies. PXB mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes and have been widely used for drug discovery in drug metabolism and pharmacokinetics studies. In the present study, we examined in vivo and in vitro DDIs between rosuvastatin and cyclosporine A in PXB mice and fresh human hepatocytes (PXB cells) obtained from PXB mice. We initially investigated the active transport of rosuvastatin into PXB cells, and found concentration-dependent uptake with a Michaelis-Menten constant value of 4.0 mol/l and a value of 4.63 pmol/min per 10 cells. Cyclosporine A inhibited the uptake of rosuvastatin with an IC value of 0.21 mol/l. We then examined in vivo DDIs, and the exposure of orally administered rosuvastatin increased by 3.3-fold and 11-fold in PXB mice pretreated with 10 and 50 mg/kg cyclosporine A, whereas it increased by 2.5-fold and 6.2-fold when rosuvastatin was administered intravenously, in studies that were conducted for considering gastrointestinal DDIs. The liver-to-blood concentration ratio of rosuvastatin was dose-dependently decreased by pretreatment with cyclosporine A in PXB mice and SCID mice. Observed DDIs in vivo were considered to be reasonable based on the estimated concentrations of cyclosporine A at the inlet to the liver and in the liver tissues of both mice. In conclusion, our results indicate that PXB mice might be a useful tool for predicting human OATP-mediated DDIs in drug discovery, and its limitation due to the differences of gastrointestinal condition from human should also be considered.

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Chimeric Mice with Humanized Livers: A Unique Tool for in Vivo and in Vitro Enzyme Induction Studies

Cited by 42 publications

References 24 publications

Visualization of Time-Dependent Distribution of Rifampicin in Rat Brain Using MALDI MSI and Quantitative LCMS/MS

Visualization of Time-Dependent Distribution of Rifampicin in Rat Brain Using MALDI MSI and Quantitative LCMS/MS

Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study

Organic Anion–Transporting Polypeptide (OATP)–Mediated Drug-Drug Interaction Study between Rosuvastatin and Cyclosporine A in Chimeric Mice with Humanized Liver

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