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Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue

Zoe Coombes, Katie Plant, Cristina Freire, Abdul W. Basit, Philip Butler, Steve Conlan Orcid Logo, Deya Gonzalez Orcid Logo

Pharmaceutics, Volume: 13, Issue: 10, Start page: 1707

Swansea University Authors: Steve Conlan Orcid Logo, Deya Gonzalez Orcid Logo

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DOI (Published version): 10.3390/pharmaceutics13101707

Abstract

Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on p...

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Published in: Pharmaceutics
ISSN: 1999-4923
Published: MDPI AG 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa58361
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last_indexed 2021-10-30T03:23:32Z
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After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. 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spelling 2021-10-29T12:46:22.8701812 v2 58361 2021-10-16 Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false bafdf635eb81280304eedf4b18e65d4e 0000-0002-1838-6752 Deya Gonzalez Deya Gonzalez true false 2021-10-16 MEDS Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens. Journal Article Pharmaceutics 13 10 1707 MDPI AG 1999-4923 progesterone; intestinal metabolism; liver metabolism; aldo keto reductase; AKR; aldehyde oxidase; AOX 16 10 2021 2021-10-16 10.3390/pharmaceutics13101707 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Knowledge Economy and Skills Scholarship to Swansea University under grant code 80300, Cyprotex Ltd. and Kuecept Ltd. 2021-10-29T12:46:22.8701812 2021-10-16T21:41:57.6883295 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Zoe Coombes 1 Katie Plant 2 Cristina Freire 3 Abdul W. Basit 4 Philip Butler 5 Steve Conlan 0000-0002-2562-3461 6 Deya Gonzalez 0000-0002-1838-6752 7 58361__21343__8b9a91453ba44d18a73eae26d41d4a86.pdf 58361.pdf 2021-10-28T14:50:58.4550583 Output 2387638 application/pdf Version of Record true © 2021 by the authors.This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
spellingShingle Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
Steve Conlan
Deya Gonzalez
title_short Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
title_full Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
title_fullStr Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
title_full_unstemmed Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
title_sort Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
author_id_str_mv 0bb6bd247e32fb4249de62c0013b51cb
bafdf635eb81280304eedf4b18e65d4e
author_id_fullname_str_mv 0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
bafdf635eb81280304eedf4b18e65d4e_***_Deya Gonzalez
author Steve Conlan
Deya Gonzalez
author2 Zoe Coombes
Katie Plant
Cristina Freire
Abdul W. Basit
Philip Butler
Steve Conlan
Deya Gonzalez
format Journal article
container_title Pharmaceutics
container_volume 13
container_issue 10
container_start_page 1707
publishDate 2021
institution Swansea University
issn 1999-4923
doi_str_mv 10.3390/pharmaceutics13101707
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens.
published_date 2021-10-16T05:10:16Z
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