Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans‐chromosomic mouse line expressing human UGT2 enzymes
Abstract UDP‐glucuronosyltransferases (UGTs) catalyze the conjugation of various substrates with sugars. Since the UGT2 family forms a large cluster spanning 1.5 Mb, transgenic mouse lines carrying the entire human UGT2 family have not been constructed because of limitations in conventional cloning...
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| Format: | Article |
| Language: | English |
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Wiley
2022-12-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.1030 |
| _version_ | 1828115693338361856 |
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| author | Kaoru Kobayashi Tsuneo Deguchi Satoshi Abe Naoyo Kajitani Kanako Kazuki Shoko Takehara Kazuomi Nakamura Atsushi Kurihara Mitsuo Oshimura Yasuhiro Kazuki |
| author_facet | Kaoru Kobayashi Tsuneo Deguchi Satoshi Abe Naoyo Kajitani Kanako Kazuki Shoko Takehara Kazuomi Nakamura Atsushi Kurihara Mitsuo Oshimura Yasuhiro Kazuki |
| author_sort | Kaoru Kobayashi |
| collection | DOAJ |
| description | Abstract UDP‐glucuronosyltransferases (UGTs) catalyze the conjugation of various substrates with sugars. Since the UGT2 family forms a large cluster spanning 1.5 Mb, transgenic mouse lines carrying the entire human UGT2 family have not been constructed because of limitations in conventional cloning techniques. Therefore, we made a humanized mouse model for UGT2 by chromosome engineering technologies. The results showed that six UGT2 isoforms examined were expressed in the liver of adult humanized UGT2 (hUGT2) mice. Thus, the functions of human UGT2B7 in the liver of hUGT2 mice were evaluated. Glucuronide of azidothymidine (AZT, zidovudine), a typical UGT2B7 substrate, was formed in the liver microsomes of hUGT2 mice but not in the liver microsomes of wild‐type and Ugt2‐knockout mice. When AZT was intravenously administered, AZT glucuronide was detected in the bile and urine of hUGT2 mice, but it was not detected in the bile and urine of wild‐type and Ugt2‐knockout mice. These results indicated that the hUGT2 mice express functional human UGT2B7 in the liver. This finding was also confirmed by using gemfibrozil as an alternative UGT2B7 substrate. Gemfibrozil glucuronide was formed in the liver microsomes of hUGT2 mice and was mainly excreted in the bile of hUGT2 mice after intravenous dosing of gemfibrozil. This hUGT2 mouse model will enable improved predictions of pharmacokinetics, urinary and biliary excretion and drug–drug interactions mediated by human UGT2, at least UGT2B7, in drug development research and basic research. |
| first_indexed | 2024-04-11T12:44:22Z |
| format | Article |
| id | doaj.art-8792878571ce483887e7d51d35ed617c |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-04-11T12:44:22Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-8792878571ce483887e7d51d35ed617c2022-12-22T04:23:24ZengWileyPharmacology Research & Perspectives2052-17072022-12-01106n/an/a10.1002/prp2.1030Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans‐chromosomic mouse line expressing human UGT2 enzymesKaoru Kobayashi0Tsuneo Deguchi1Satoshi Abe2Naoyo Kajitani3Kanako Kazuki4Shoko Takehara5Kazuomi Nakamura6Atsushi Kurihara7Mitsuo Oshimura8Yasuhiro Kazuki9Department of Biopharmaceutics, Graduate School of Clinical Pharmacy Meiji Pharmaceutical University Kiyose, Tokyo JapanDrug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. Chuo‐ku, Tokyo JapanChromosome Engineering Research Center (CERC) Tottori University Yonago, Tottori JapanChromosome Engineering Research Center (CERC) Tottori University Yonago, Tottori JapanChromosome Engineering Research Center (CERC) Tottori University Yonago, Tottori JapanChromosome Engineering Research Center (CERC) Tottori University Yonago, Tottori JapanAdvanced Medicine, Innovation and Clinical Research Center Tottori University Hospital Yonago, Tottori JapanDrug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. Chuo‐ku, Tokyo JapanChromosome Engineering Research Center (CERC) Tottori University Yonago, Tottori JapanChromosome Engineering Research Center (CERC) Tottori University Yonago, Tottori JapanAbstract UDP‐glucuronosyltransferases (UGTs) catalyze the conjugation of various substrates with sugars. Since the UGT2 family forms a large cluster spanning 1.5 Mb, transgenic mouse lines carrying the entire human UGT2 family have not been constructed because of limitations in conventional cloning techniques. Therefore, we made a humanized mouse model for UGT2 by chromosome engineering technologies. The results showed that six UGT2 isoforms examined were expressed in the liver of adult humanized UGT2 (hUGT2) mice. Thus, the functions of human UGT2B7 in the liver of hUGT2 mice were evaluated. Glucuronide of azidothymidine (AZT, zidovudine), a typical UGT2B7 substrate, was formed in the liver microsomes of hUGT2 mice but not in the liver microsomes of wild‐type and Ugt2‐knockout mice. When AZT was intravenously administered, AZT glucuronide was detected in the bile and urine of hUGT2 mice, but it was not detected in the bile and urine of wild‐type and Ugt2‐knockout mice. These results indicated that the hUGT2 mice express functional human UGT2B7 in the liver. This finding was also confirmed by using gemfibrozil as an alternative UGT2B7 substrate. Gemfibrozil glucuronide was formed in the liver microsomes of hUGT2 mice and was mainly excreted in the bile of hUGT2 mice after intravenous dosing of gemfibrozil. This hUGT2 mouse model will enable improved predictions of pharmacokinetics, urinary and biliary excretion and drug–drug interactions mediated by human UGT2, at least UGT2B7, in drug development research and basic research.https://doi.org/10.1002/prp2.1030gemfibrozilmouse modelUGT2zidovudine |
| spellingShingle | Kaoru Kobayashi Tsuneo Deguchi Satoshi Abe Naoyo Kajitani Kanako Kazuki Shoko Takehara Kazuomi Nakamura Atsushi Kurihara Mitsuo Oshimura Yasuhiro Kazuki Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans‐chromosomic mouse line expressing human UGT2 enzymes Pharmacology Research & Perspectives gemfibrozil mouse model UGT2 zidovudine |
| title | Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans‐chromosomic mouse line expressing human UGT2 enzymes |
| title_full | Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans‐chromosomic mouse line expressing human UGT2 enzymes |
| title_fullStr | Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans‐chromosomic mouse line expressing human UGT2 enzymes |
| title_full_unstemmed | Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans‐chromosomic mouse line expressing human UGT2 enzymes |
| title_short | Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans‐chromosomic mouse line expressing human UGT2 enzymes |
| title_sort | analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans chromosomic mouse line expressing human ugt2 enzymes |
| topic | gemfibrozil mouse model UGT2 zidovudine |
| url | https://doi.org/10.1002/prp2.1030 |
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