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In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole

Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5α-reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid c...

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Autores principales: Seo, Seong-Wook, Park, Jin Woo, Han, Dong-Gyun, Kim, Ji-Min, Kim, Sanghyun, Park, Taeuk, Kang, Kyung-Hwa, Yang, Min Hye, Yoon, In-Soo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956158/
https://www.ncbi.nlm.nih.gov/pubmed/31835695
http://dx.doi.org/10.3390/pharmaceutics11120673
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author Seo, Seong-Wook
Park, Jin Woo
Han, Dong-Gyun
Kim, Ji-Min
Kim, Sanghyun
Park, Taeuk
Kang, Kyung-Hwa
Yang, Min Hye
Yoon, In-Soo
author_facet Seo, Seong-Wook
Park, Jin Woo
Han, Dong-Gyun
Kim, Ji-Min
Kim, Sanghyun
Park, Taeuk
Kang, Kyung-Hwa
Yang, Min Hye
Yoon, In-Soo
author_sort Seo, Seong-Wook
collection PubMed
description Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5α-reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid chromatography with fluorescence detection (HPLC-FL) method for simultaneous determination of DUT and its major active metabolite, 6β-hydroxydutasteride (H-DUT). Next, the pharmacokinetic interactions of DUT with ketoconazole (KET), a potent CYP3A inhibitor, were comprehensively investigated. In vivo rat intravenous and oral studies revealed that the pharmacokinetics of DUT and H-DUT were significantly altered by the co-administration of KET. Furthermore, the in vitro microsomal metabolism, blood distribution, and protein-binding studies suggest that the altered pharmacokinetics of DUT could be attributed primarily to the inhibition of the DUT metabolism by KET. To the best of our knowledge, this is the first study to show the drug interaction potential of DUT with azole antifungal drugs including KET, together with a newly developed HPLC-FL method for the simultaneous quantification of DUT and H-DUT.
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spelling pubmed-69561582020-01-23 In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole Seo, Seong-Wook Park, Jin Woo Han, Dong-Gyun Kim, Ji-Min Kim, Sanghyun Park, Taeuk Kang, Kyung-Hwa Yang, Min Hye Yoon, In-Soo Pharmaceutics Article Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5α-reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid chromatography with fluorescence detection (HPLC-FL) method for simultaneous determination of DUT and its major active metabolite, 6β-hydroxydutasteride (H-DUT). Next, the pharmacokinetic interactions of DUT with ketoconazole (KET), a potent CYP3A inhibitor, were comprehensively investigated. In vivo rat intravenous and oral studies revealed that the pharmacokinetics of DUT and H-DUT were significantly altered by the co-administration of KET. Furthermore, the in vitro microsomal metabolism, blood distribution, and protein-binding studies suggest that the altered pharmacokinetics of DUT could be attributed primarily to the inhibition of the DUT metabolism by KET. To the best of our knowledge, this is the first study to show the drug interaction potential of DUT with azole antifungal drugs including KET, together with a newly developed HPLC-FL method for the simultaneous quantification of DUT and H-DUT. MDPI 2019-12-11 /pmc/articles/PMC6956158/ /pubmed/31835695 http://dx.doi.org/10.3390/pharmaceutics11120673 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Seo, Seong-Wook
Park, Jin Woo
Han, Dong-Gyun
Kim, Ji-Min
Kim, Sanghyun
Park, Taeuk
Kang, Kyung-Hwa
Yang, Min Hye
Yoon, In-Soo
In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole
title In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole
title_full In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole
title_fullStr In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole
title_full_unstemmed In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole
title_short In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole
title_sort in vitro and in vivo assessment of metabolic drug interaction potential of dutasteride with ketoconazole
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956158/
https://www.ncbi.nlm.nih.gov/pubmed/31835695
http://dx.doi.org/10.3390/pharmaceutics11120673
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