Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue

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.

Biotransformation of Δ1-Progesterone Using Selected Entomopathogenic Filamentous Fungi and Prediction of Its Products’ Bioactivity

“…Based on the insight provided by the NMR spectra, it was determined that, compared to compound 6, in the structure of compound 7, the structural modification occurred only within the D ring. The absence of a signal in the 1 H NMR and 13 C NMR spectra coming from the C-21 methyl group and the presence of a triplet at 3.64 ppm (coming from proton H-17α visible on the 1 H NMR), which couples with the signal coming from carbon C-17 in the HMQC spectrum, clearly indicate that the obtained product is 6β,17β-dihydroxyandrost-1,4-diene-3-one (7), i.e., 6β-hydroxy-Δ 1 -testosterone (Supplementary Materials: Figures S31-S35). Similar mechanisms are known in the available literature, involving subsequent oxidations leading to the degradation of the acyl substituent located at the C-17 carbon of progesterone.…”

“…To evaluate the physicochemical properties, pharmacokinetics, and potential biological activity of Δ 1 -progesterone derivatives, cheminformatic tools such as SwissADME and passOnline were employed. Physicochemical descriptor calculations were conducted for both the substrate and the obtained products (2)(3)(4)(5)(6)(7)(8), as summarized in Table 3. Predictions encompassed their ADME parameters (absorption, distribution, metabolism, and excretion), pharmacokinetic properties, and suitability for medicinal chemistry.…”

“…The need for such elevated doses serves as an indicative factor of the low bioavailability within this category of sex steroids [70]. In addition, the described products (3)(4)(5)(6)(7)(8) should not be inhibitors of monooxygenases necessary for the proper functioning of the human body. Based on the predicted pharmacokinetic and pharmacodynamic data (Table 3), 11α-hydroxypregn-1,4-diene-3,20-dione (3), 6β,11α-dihydroxypregn-1,4-diene-3,20-dione (4), 6β-hydroxypregn-1,4-diene-3,11,20trione (5), 6β,17α-dihydroxypregn-1,4-diene-3,20-dione ( 6), 6β,17β-dihydroxyandrost-1,4diene-3-one (7), and 12β,17α-dihydroxypregn-1,4-diene-3,20-dione ( 8) can be considered as potential drugs [64].…”

“…There is increasing evidence that many metabolites are not inactive but have important biological effects [ 4 , 5 , 6 ]. Progesterone is rapidly and extensively metabolized in the human body, mainly in the liver, but also in the brain, skin, and various other extrahepatic tissues [ 7 , 8 ]. Progesterone exhibits a remarkably short elimination half-life of approximately 5 min in the circulatory system.…”

Nanonized progesterone formulation for improved oral bioavailability in healthy and pregnant rabbits

“…It is classified as Class ІІ drug by Biopharmaceutical Classification System (BCS) with high lipophilicity (Log P = 3.9) and very low aqueous solubility (10 mg/mL) [10]. Further, it also undergoes hepatic metabolism when given by oral route [11]. A higher dose of PG shows extensive side effects such as dizziness or somnolence.…”