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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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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa58361
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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 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.
Keywords: progesterone; intestinal metabolism; liver metabolism; aldo keto reductase; AKR; aldehyde oxidase; AOX
College: Swansea University Medical School
Funders: Knowledge Economy and Skills Scholarship to Swansea University under grant code 80300, Cyprotex Ltd. and Kuecept Ltd.
Issue: 10
Start Page: 1707