Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue.

Zoe Coombes,Philip Butler,Deyarina Gonzalez,Cristina Freire,Katie Plant,R Steven Conlan,Abdul W Basit

doi:10.3390/pharmaceutics13101707

Zoe Coombes, Philip Butler + Show 5 more

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https://doi.org/10.3390/pharmaceutics13101707

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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.

Highlights

Introduction published maps and institutional affilNatural progesterone (Figure 1) is a highly permeable, poorly soluble steroid hormone which is found endogenously in both males and females
Understanding the kinetics of progesterone depletion during first-pass metabolism in the liver and intestines is, important to consider whilst developing new oral formulations
This study looked at the rate of progesterone depletion in human and rat liver, and in intestinal preparations

Summary

Introduction

Introduction published maps and institutional affilNatural progesterone (Figure 1) is a highly permeable, poorly soluble steroid hormone which is found endogenously in both males and females. Progesterone maintains pregnancy and modulates the menstrual cycle; and in males, progesterone influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. In both genders, it exerts cerebroprotective effects and potentiates neural myelination [1]. When taken orally for release in the upper gastrointestinal (GI) tract, natural progesterone has very low bio-availability due to its poor absorption and extensive pre-systemic metabolism. This leads to considerable variability in the pharmacokinetics of progesterone among individuals [3].

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