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Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue
Pharmaceutics, Volume: 13, Issue: 10, Start page: 1707
Swansea University Authors:
Steve Conlan , Deya Gonzalez
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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...
Published in: | Pharmaceutics |
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ISSN: | 1999-4923 |
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MDPI AG
2021
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URI: | https://cronfa.swan.ac.uk/Record/cronfa58361 |
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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 BMS 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 Biomedical Sciences COLLEGE CODE BMS 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 |
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13 |
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1707 |
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2021 |
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Swansea University |
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1999-4923 |
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10.3390/pharmaceutics13101707 |
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MDPI AG |
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Faculty of Medicine, Health and Life Sciences |
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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 |
2021-10-16T04:14:50Z |
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1763753999964569600 |
score |
11.021648 |