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Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro

Naftopidil (NAF) is widely used for the treatment of benign prostatic hyperplasia and prevention of prostate cancer in elderly men. These patients receive a combination of drugs, which involves high risk for drug–drug interaction. NAF exhibits superior efficacy but must be administered at a much hig...

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Autores principales: Liu, Xia-Wen, Rong, Yi, Zhang, Xing-Fei, Huang, Jun-Jun, Cai, Yi, Huang, Bi-Yun, Zhu, Liu, Wu, Bo, Hou, Ning, Luo, Cheng-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769128/
https://www.ncbi.nlm.nih.gov/pubmed/29375383
http://dx.doi.org/10.3389/fphar.2017.00984
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author Liu, Xia-Wen
Rong, Yi
Zhang, Xing-Fei
Huang, Jun-Jun
Cai, Yi
Huang, Bi-Yun
Zhu, Liu
Wu, Bo
Hou, Ning
Luo, Cheng-Feng
author_facet Liu, Xia-Wen
Rong, Yi
Zhang, Xing-Fei
Huang, Jun-Jun
Cai, Yi
Huang, Bi-Yun
Zhu, Liu
Wu, Bo
Hou, Ning
Luo, Cheng-Feng
author_sort Liu, Xia-Wen
collection PubMed
description Naftopidil (NAF) is widely used for the treatment of benign prostatic hyperplasia and prevention of prostate cancer in elderly men. These patients receive a combination of drugs, which involves high risk for drug–drug interaction. NAF exhibits superior efficacy but must be administered at a much higher dosage than other therapeutic drugs. We previously showed that extensive glucuronidation of NAF enantiomers caused poor bioavailability. However, the metabolic pathway and mechanism of action of NAF enantiomer remain to be elucidated. The present study was performed to identify the human UDP-glucuronosyltransferases (UGTs) responsible for the glucuronidation of NAF enantiomers and to investigate the potential inhibition of UGT activity by NAF. The major metabolic sites examined were liver and kidney, which were compared with intestine. Screening of 12 recombinant UGTs showed that UGT2B7 primarily contributed to the metabolism of both enantiomers. Moreover, enzyme kinetics for R(+)-NAF, UGT2B7 (mean K(m), 21 μM; mean V(max), 1043 pmol/min/mg) showed significantly higher activity than observed for UGT2B4 and UGT1A9. UGT2B4 (mean K(m), 55 μM; mean V(max), 1976 pmol/min/mg) and UGT2B7 (mean K(m), 38 μM; mean V(max), 1331 pmol/min/mg) showed significantly higher catalysis of glucuronidation of S(-)-NAF than UGT1A9. In human liver microsomes, R(+)-NAF and S(-)-NAF also inhibited UGT1A9: mean K(i) values for R(+)-NAF and S(-)-NAF were 10.0 μM and 11.5 μM, respectively. These data indicate that UGT2B7 was the principal enzyme mediating glucuronidation of R(+)-NAF and S(-)-NAF. UGT2B4 plays the key role in the stereoselective metabolism of NAF enantiomers. R(+)-NAF and S(-)-NAF may inhibit UGT1A9. Understanding the metabolism of NAF enantiomers, especially their interactions with metabolic enzymes, will help to elucidate potential drug–drug interactions and to optimize the administration of this medicine.
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spelling pubmed-57691282018-01-26 Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro Liu, Xia-Wen Rong, Yi Zhang, Xing-Fei Huang, Jun-Jun Cai, Yi Huang, Bi-Yun Zhu, Liu Wu, Bo Hou, Ning Luo, Cheng-Feng Front Pharmacol Pharmacology Naftopidil (NAF) is widely used for the treatment of benign prostatic hyperplasia and prevention of prostate cancer in elderly men. These patients receive a combination of drugs, which involves high risk for drug–drug interaction. NAF exhibits superior efficacy but must be administered at a much higher dosage than other therapeutic drugs. We previously showed that extensive glucuronidation of NAF enantiomers caused poor bioavailability. However, the metabolic pathway and mechanism of action of NAF enantiomer remain to be elucidated. The present study was performed to identify the human UDP-glucuronosyltransferases (UGTs) responsible for the glucuronidation of NAF enantiomers and to investigate the potential inhibition of UGT activity by NAF. The major metabolic sites examined were liver and kidney, which were compared with intestine. Screening of 12 recombinant UGTs showed that UGT2B7 primarily contributed to the metabolism of both enantiomers. Moreover, enzyme kinetics for R(+)-NAF, UGT2B7 (mean K(m), 21 μM; mean V(max), 1043 pmol/min/mg) showed significantly higher activity than observed for UGT2B4 and UGT1A9. UGT2B4 (mean K(m), 55 μM; mean V(max), 1976 pmol/min/mg) and UGT2B7 (mean K(m), 38 μM; mean V(max), 1331 pmol/min/mg) showed significantly higher catalysis of glucuronidation of S(-)-NAF than UGT1A9. In human liver microsomes, R(+)-NAF and S(-)-NAF also inhibited UGT1A9: mean K(i) values for R(+)-NAF and S(-)-NAF were 10.0 μM and 11.5 μM, respectively. These data indicate that UGT2B7 was the principal enzyme mediating glucuronidation of R(+)-NAF and S(-)-NAF. UGT2B4 plays the key role in the stereoselective metabolism of NAF enantiomers. R(+)-NAF and S(-)-NAF may inhibit UGT1A9. Understanding the metabolism of NAF enantiomers, especially their interactions with metabolic enzymes, will help to elucidate potential drug–drug interactions and to optimize the administration of this medicine. Frontiers Media S.A. 2018-01-11 /pmc/articles/PMC5769128/ /pubmed/29375383 http://dx.doi.org/10.3389/fphar.2017.00984 Text en Copyright © 2018 Liu, Rong, Zhang, Huang, Cai, Huang, Zhu, Wu, Hou and Luo. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Liu, Xia-Wen
Rong, Yi
Zhang, Xing-Fei
Huang, Jun-Jun
Cai, Yi
Huang, Bi-Yun
Zhu, Liu
Wu, Bo
Hou, Ning
Luo, Cheng-Feng
Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro
title Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro
title_full Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro
title_fullStr Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro
title_full_unstemmed Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro
title_short Human UDP-Glucuronosyltransferase 2B4 and 2B7 Are Responsible for Naftopidil Glucuronidation in Vitro
title_sort human udp-glucuronosyltransferase 2b4 and 2b7 are responsible for naftopidil glucuronidation in vitro
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769128/
https://www.ncbi.nlm.nih.gov/pubmed/29375383
http://dx.doi.org/10.3389/fphar.2017.00984
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