Approach for in Vivo Protein Binding of 5-n-Butyl-pyrazolo[1,5-a]pyrimidine Bioactivated in Chimeric Mice with Humanized Liver by Two-Dimensional Electrophoresis with Accelerator Mass Spectrometry

Yamazaki, Hiroshi; Kuribayashi, Shunji; Inoue, Takato; Tateno, Chise; Nishikura, Yasufumi; Oofusa, Ken; Harada, Daisuke; Naito, Shinsaku; Horie, Tetsuhiro; Ohta, Shigeru

doi:10.1021/tx900323a

Cited by 33 publications

(45 citation statements)

References 24 publications

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“…17) OT-7100, which is known to be toxic in humans but not in mice, was activated to reactive intermediate(s) in the chimeric mice with humanized liver. 21) This animal should provide a good model for investigating drug toxicity in vivo in preclinical studies. The chimeric mice also exhibited CYP3A-induction on treatment of rifampicin and rifabutin.…”

Section: Resultsmentioning

confidence: 99%

“…Chimeric mice with humanized liver preferentially yielded M-23OH and its glutathione conjugate in the plasma and liver. 21) In contrast, liver microsomes from chimeric mice with rat liver yielded some rat-specific metabolites in vivo.…”

Section: In Vivo Toxicity In Chimeric Micementioning

confidence: 97%

“…Only M-23OH was detected in human liver microsomal incubation, but M-23OH and M-22OH were seen in rat liver microsomal incubation. 21) Prior to docking simulation, the energy of rat P450 1A2 was minimized using the CHARM22 force field in the MOE software package (ver. 2008.10, Chemical Computing Group, Montreal, Canada) based on the structure of human P450 1A2 (Protein Data Bank code, 2HI4) to model the three-dimensional structure.…”

Section: In Vivo Toxicity In Chimeric Micementioning

confidence: 99%

“…Development of potential analgesic agent 5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine (OT-7100) was cancelled because of limited hepatotoxic effects in humans that had not been predicted from studies in regulatory animals such as rats or in vitro studies. 21) Human liver microsomal CYP1A2 was able to effectively mediate the transformation of a primary metabolite 5-n-butyl-pyrazolo[1,5-a]pyrimidine (M-5) to 3-hydroxy-5-n-butyl-pyrazolo[1,5-a]pyrimidine (M-23OH), yielding a possible quinine-imine metabolite that could bind to glutathione or biomolecules such as CYP1A2 and other proteins in livers (Fig. 1).…”

Section: In Vivo Toxicity In Chimeric Micementioning

confidence: 99%

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Drug Metabolism and Toxicity in Chimeric Mice with Humanized Liver

Emoto

Iwasaki

Murayama

et al. 2011

JOURNAL OF HEALTH SCIENCE

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The cytochrome P450 (P450, CYP) enzyme superfamily is associated with the metabolism of drugs, environmental pollutants and endogenous substrates with broad overlapping substrate specificities. In addition, species differences between experimental animals and humans in the roles of P450 enzymes in drug metabolism are determinant factors in the drug discovery process. The induction and inhibition of P450-dependent metabolism, especially in the case of P450 3A enzyems, can cause serious problems in clinical practice and in the attrition of drug candidates because of adverse toxicology or pharmacokinetics. Recently, chimeric mice whose livers have been replaced to a level of 80% or more with human hepatocytes were established using urokinase-type plasminogen activator transgenic/severe combined immunodeficiency (uPA/SCID) mice. In the livers of these chimeric mice, hepatic cords and sinusoid-like structures were observed. Moreover, bile canaliculi associated with human hepatocytes were also detected. The mRNA expressions derived from humans of 52 phase I and 26 phase II enzymes (including 20 P450 s) and 21 transporters were ascertained in the chimeric mice liver. Taken together, these chimeric mice exhibited the glutathione conjugate form of a possible quinine-imine metabolite and responded to treatment with rifampicin or rifabutin by induction of P450 3A enzyems. This animal model should prove to be a good in vivo tool to assess the safety of drug candidates in terms of toxicity and drug-drug interactions caused by P450 induction.

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Section: Resultsmentioning

confidence: 99%

Section: In Vivo Toxicity In Chimeric Micementioning

confidence: 97%

Section: In Vivo Toxicity In Chimeric Micementioning

confidence: 99%

Section: In Vivo Toxicity In Chimeric Micementioning

confidence: 99%

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Drug Metabolism and Toxicity in Chimeric Mice with Humanized Liver

Emoto

Iwasaki

Murayama

et al. 2011

JOURNAL OF HEALTH SCIENCE

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“…In these mice, approximately 80% of the hepatocytes are human. The expression levels and metabolic activities of P450 and non-P450 enzymes in livers of PXB mice with a high replacement index (RI) are similar to those of humans (Katoh et al, 2004(Katoh et al, , 2005, and human-specific metabolites are formed in PXB mice (Inoue et al, 2009;Kamimura et al, 2010;Yamazaki et al, 2010;De Serres et al, 2011). Thus, PXB mice could be a good in vivo model for predicting drug metabolism in humans.…”

Section: Introductionmentioning

confidence: 99%

Prediction of In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver

Sanoh

Horiguchi²,

Sugihara³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Accurate prediction of pharmacokinetics (PK) parameters in humans from animal data is difficult for various reasons, including species differences. However, chimeric mice with humanized liver (PXB mice; urokinase-type plasminogen activator/severe combined immunodeficiency mice repopulated with approximately 80% human hepatocytes) have been developed. The expression levels and metabolic activities of cytochrome P450 (P450) and non-P450 enzymes in the livers of PXB mice are similar to those in humans. In this study, we examined the predictability for human PK parameters from data obtained in PXB mice. Elimination of selected drugs involves multiple metabolic pathways mediated not only by P450 but also by non-P450 enzymes, such as UDP-glucuronosyltransferase, sulfotransferase, and aldehyde oxidase in liver. ). Elimination half-life (t 1/2 ) after intravenous administration also showed a good correlation (r 2 ‫؍‬ 0.886, p ‫؍‬ 1.506 ؋ 10 ؊4) between humans and PXB mice. The rank order of CL and t 1/2 in human could be predicted at least, although it may not be possible to predict absolute values due to rather large prediction errors. Our results indicate that in vitro and in vivo experiments with PXB mice should be useful at least for semiquantitative prediction of the PK characteristics of candidate drugs in humans.

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Proteomics in Drug Discovery and Development

Wang

Witzmann

2012

Encyclopedia of Drug Metabolism and Interactions

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Aided by major technological advances, the field of proteomics has become extremely active in the identification of drug targets that can guide drug development and treatment decisions and ultimately improve treatment outcomes. Proteomics has provided a means for molecular profiling that will assist in the development of tailored therapies. Although the implementation of genomic and proteomic testing in clinical practice is still in its infancy, the rapid development of new technologies and platforms provides hope for personalized medicine. This chapter describes these technologies and platforms, presenting many of their technical aspects along with examples of how they have been implemented in pharmaceutical applications.

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Approach for in Vivo Protein Binding of 5-n-Butyl-pyrazolo[1,5-a]pyrimidine Bioactivated in Chimeric Mice with Humanized Liver by Two-Dimensional Electrophoresis with Accelerator Mass Spectrometry

Cited by 33 publications

References 24 publications

Drug Metabolism and Toxicity in Chimeric Mice with Humanized Liver

Drug Metabolism and Toxicity in Chimeric Mice with Humanized Liver

Prediction of In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver

Proteomics in Drug Discovery and Development

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