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Drug Metabolism & Disposition

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Prediction of Human Disproportionate and Biliary Excreted Metabolites Using Chimeric Mice with Humanized Liver

Suguru Kato, Abhi Shah, Mihaela Plesescu, Yoshinari Miyata, Jayaprakasam Bolleddula, Swapan Chowdhury and Xiaochun Zhu
Drug Metabolism and Disposition July 14, 2020, DMD-AR-2020-000128; DOI: https://doi.org/10.1124/dmd.120.000128
Suguru Kato
1Quality Development Department, Chugai Pharmaceuticals Co., Ltd., Japan
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Abhi Shah
2DMPK, Takeda Pharmaceutical Company Limited, United States
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Mihaela Plesescu
2DMPK, Takeda Pharmaceutical Company Limited, United States
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Yoshinari Miyata
3Research Planning & Business Development, PhoenixBio USA Corporation, United States
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Jayaprakasam Bolleddula
4Agios Pharmaceuticals, Inc., United States
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Swapan Chowdhury
5Takeda Pharmaceutical Co, United States of America
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Xiaochun Zhu
6DMPK, Takeda Pharmaceuticals, United States
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  • For correspondence: xiaochun.zhu@takeda.com
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Abstract

PXB-mouse is potentially a useful in vivo model to predict human hepatic metabolism and clearance. Four model compounds, [14C]desloratadine, [3H]mianserin, cyproheptadine, and [3H]carbazeran, all reported with disproportionate human metabolites were orally administered to PXB- or control SCID mice to elucidate the biotransformation of each of them. For [14C]desloratadine in PXB-mice, O-glucuronide of 3-hydroxydesloratadine was observed as the predominant metabolite in both the plasma and urine. Both 3-hydroxydesloratadine and its O-glucuronide were detected as major drug-related materials in the bile while only 3-hydroxydesloratadine was detected in the feces, suggesting that a fraction of 3-hydroxydesloratadine in feces derived from deconjugation of its O-glucuronide by gut microflora. This information can help understand the biliary clearance mechanism of a drug and may fill the gap in a human ADME study where the bile samples are typically not available. The metabolic profiles in PXB-mice were qualitatively similar to those reported in humans in a clinical study, where 3-hydroxydesloratadine and its O-glucuronide were major and disproportionate metabolites compared to rat, mouse, and monkey. In the control SCID mice, neither of the metabolites was detected in any matrix. Similarly, for the other three compounds, all human specific or disproportionate metabolites were detected at high level in PXB-mice but they were either not or minimally observed in the control mice. Data from these four compounds indicate that studies in PXB-mice can help predict potential for the presence of human disproportionate metabolites (relative to preclinical species) prior to conducting clinical studies and understand biliary clearance mechanism of a drug.

Significance Statement Studies in PXB-mice have successfully predicted the human major and disproportionate metabolites compared to preclinical safety species for desloratadine, mianserin, cyproheptadine, and carbazeran. In addition, biliary excretion data from PXB-mice can help understand human biliary clearance mechanism of a drug.

  • drug metabolism
  • metabolite identification
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (3)
Drug Metabolism and Disposition
Vol. 49, Issue 3
1 Mar 2021
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Prediction of Human Metabolites Using PXB-Mice

Suguru Kato, Abhi Shah, Mihaela Plesescu, Yoshinari Miyata, Jayaprakasam Bolleddula, Swapan Chowdhury and Xiaochun Zhu
Drug Metabolism and Disposition July 14, 2020, DMD-AR-2020-000128; DOI: https://doi.org/10.1124/dmd.120.000128

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Prediction of Human Metabolites Using PXB-Mice

Suguru Kato, Abhi Shah, Mihaela Plesescu, Yoshinari Miyata, Jayaprakasam Bolleddula, Swapan Chowdhury and Xiaochun Zhu
Drug Metabolism and Disposition July 14, 2020, DMD-AR-2020-000128; DOI: https://doi.org/10.1124/dmd.120.000128
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