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OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro
Bentysrepinine (Y101) is a novel phenylalanine dipeptide for the treatment of hepatitis B virus. Renal excretion played an important role in the elimination of Y101 and its metabolites, M8 and M9, in healthy Chinese subjects, although the molecular mechanisms of renal excretion and potential drug–dr...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9967645/ https://www.ncbi.nlm.nih.gov/pubmed/36838982 http://dx.doi.org/10.3390/molecules28041995 |
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author | Zhang, Aijie Yang, Fanlong Yuan, Yang Li, Cai Huo, Xiaokui Liu, Jing Zhou, Shenzhi Li, Wei Zhang, Na Liu, Jianfeng Dong, Shiqi Fan, Huirong Peng, Ying Zheng, Jiang |
author_facet | Zhang, Aijie Yang, Fanlong Yuan, Yang Li, Cai Huo, Xiaokui Liu, Jing Zhou, Shenzhi Li, Wei Zhang, Na Liu, Jianfeng Dong, Shiqi Fan, Huirong Peng, Ying Zheng, Jiang |
author_sort | Zhang, Aijie |
collection | PubMed |
description | Bentysrepinine (Y101) is a novel phenylalanine dipeptide for the treatment of hepatitis B virus. Renal excretion played an important role in the elimination of Y101 and its metabolites, M8 and M9, in healthy Chinese subjects, although the molecular mechanisms of renal excretion and potential drug–drug interactions (DDIs) remain unclear. The present study aimed to determine the organic anion transporters (OATs) involved in the renal disposition of Y101 and to predict the potential DDI between Y101 and entecavir, the first-line agent against HBV and a substrate of OAT1/3. Pharmacokinetic studies and uptake assays using rat kidney slices, as well as hOAT1/3-HEK293 cells, were performed to evaluate potential DDI. The co-administration of probenecid (an inhibitor of OATs) significantly increased the plasma concentrations and area under the plasma concentration–time curves of M8 and M9 but not Y101, while reduced renal clearance and the cumulative urinary excretion of M8 were observed in rats. The time course of Y101 and M8 uptake via rat kidney slices was temperature-dependent. Moreover, the uptake of M8 was inhibited significantly by probenecid and benzylpenicillin, but not by p-aminohippurate or tetraethyl ammonium. M8 was found to be a substrate of hOAT3, but Y101 is not a substrate of either hOAT1 or hOAT3. Additionally, the entecavir inhibited the uptake of M8 in the hOAT3-transfected cells and rat kidney slices in vitro. Interestingly, no significant changes were observed in the pharmacokinetic parameters of Y101, M8 or entecavir, regardless of intravenous or oral co-administration of Y101 and entecavir in rats. In conclusion, M8 is a substrate of OAT3 in rats and humans. Furthermore, M8 also mediates the DDI between Y101 and entecavir in vitro, mediated by OAT3. We speculate that it would be safe to use Y101 with entecavir in clinical practice. Our results provide useful information with which to predict the DDIs between Y101 and other drugs that act as substrates of OAT3. |
format | Online Article Text |
id | pubmed-9967645 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99676452023-02-27 OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro Zhang, Aijie Yang, Fanlong Yuan, Yang Li, Cai Huo, Xiaokui Liu, Jing Zhou, Shenzhi Li, Wei Zhang, Na Liu, Jianfeng Dong, Shiqi Fan, Huirong Peng, Ying Zheng, Jiang Molecules Article Bentysrepinine (Y101) is a novel phenylalanine dipeptide for the treatment of hepatitis B virus. Renal excretion played an important role in the elimination of Y101 and its metabolites, M8 and M9, in healthy Chinese subjects, although the molecular mechanisms of renal excretion and potential drug–drug interactions (DDIs) remain unclear. The present study aimed to determine the organic anion transporters (OATs) involved in the renal disposition of Y101 and to predict the potential DDI between Y101 and entecavir, the first-line agent against HBV and a substrate of OAT1/3. Pharmacokinetic studies and uptake assays using rat kidney slices, as well as hOAT1/3-HEK293 cells, were performed to evaluate potential DDI. The co-administration of probenecid (an inhibitor of OATs) significantly increased the plasma concentrations and area under the plasma concentration–time curves of M8 and M9 but not Y101, while reduced renal clearance and the cumulative urinary excretion of M8 were observed in rats. The time course of Y101 and M8 uptake via rat kidney slices was temperature-dependent. Moreover, the uptake of M8 was inhibited significantly by probenecid and benzylpenicillin, but not by p-aminohippurate or tetraethyl ammonium. M8 was found to be a substrate of hOAT3, but Y101 is not a substrate of either hOAT1 or hOAT3. Additionally, the entecavir inhibited the uptake of M8 in the hOAT3-transfected cells and rat kidney slices in vitro. Interestingly, no significant changes were observed in the pharmacokinetic parameters of Y101, M8 or entecavir, regardless of intravenous or oral co-administration of Y101 and entecavir in rats. In conclusion, M8 is a substrate of OAT3 in rats and humans. Furthermore, M8 also mediates the DDI between Y101 and entecavir in vitro, mediated by OAT3. We speculate that it would be safe to use Y101 with entecavir in clinical practice. Our results provide useful information with which to predict the DDIs between Y101 and other drugs that act as substrates of OAT3. MDPI 2023-02-20 /pmc/articles/PMC9967645/ /pubmed/36838982 http://dx.doi.org/10.3390/molecules28041995 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zhang, Aijie Yang, Fanlong Yuan, Yang Li, Cai Huo, Xiaokui Liu, Jing Zhou, Shenzhi Li, Wei Zhang, Na Liu, Jianfeng Dong, Shiqi Fan, Huirong Peng, Ying Zheng, Jiang OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro |
title | OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro |
title_full | OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro |
title_fullStr | OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro |
title_full_unstemmed | OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro |
title_short | OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro |
title_sort | oat3 participates in drug–drug interaction between bentysrepinine and entecavir through interactions with m8—a metabolite of bentysrepinine—in rats and humans in vitro |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9967645/ https://www.ncbi.nlm.nih.gov/pubmed/36838982 http://dx.doi.org/10.3390/molecules28041995 |
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