Ecdysteroid metabolism in mammals: The fate of ingested 20-hydroxyecdysone in mice and rats

Dinan, Laurence; Balducci, Christine; Guibout, Louis; Foucault, Anne-Sophie; Bakrim, Ahmed; Kumpun, Saowanee; Girault, Jean‐Pierre; Tourette, Cendrine; Dioh, Waly; Dilda, Pierre J.; Veillet, Stanislas; Lafont, René

doi:10.1016/j.jsbmb.2021.105896

Cited by 8 publications

(21 citation statements)

References 28 publications

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“…The only exception to this is 14d20E (which is the major initial intestinal metabolite of ingested 20E), with a TL Score of 1, owing to its lower PSA and lower number of H-bond donor groups after the removal of the 14α-hydroxyl group. This is in accord with the experimental observation that this metabolite is found in the urine of rats and mice after the ingestion of 20E, implying that at least a portion of the 14d20E formed in the large intestine is absorbed into the blood to reach the kidneys [127].…”

Section: Some Drugability Calculationssupporting

confidence: 90%

“…The elimination of ingested or injected 20E is predominantly fecal (Figure 8A,B). The microbial origin of the 14d20E metabolite is demonstrated by the absence of this metabolite in axenic rats fed 20E [129] and by its formation from 20E in incubations of intestinal contents under anaerobic conditions [127]. That 14-dehydroxylation is associated with the microbiote of the large intestine is in accord with previous findings that dehydroxylations of steroids and bile acids are only bacterial [130,131].…”

Section: Pharmacokinetics After Oral Administration In Mice-more Recent Studiessupporting

confidence: 71%

“…The metabolism of radiolabelled 20E has been more extensively studied [126,127]. These studies involved 20E radiolabelled in the nucleus, so as to be able to follow sidechain cleavage.…”

Section: Pharmacokinetics After Oral Administration In Mice-more Recent Studiesmentioning

confidence: 99%

“…1%) and Post (ca. 19%) have been determined [127,128]. As in mice, the initial fate of ingested 20E is uncomplicated, remaining almost completely associated with the gut in unchanged form, until it reaches the large intestine, where microbial metabolism and metabolism associated with the enterohepatic cycle come into play to rapidly increase the extent and diversity of metabolites.…”

Section: Pharmacokinetics After Oral Administration In Mice-more Recent Studiesmentioning

confidence: 99%

“…After oral application of [ 3 H]20E, elimination of radioactively labelled 20E and its metabolites is completed within 48 h. The amount of radioactivity recovered from the feces is by far the major route of excretion, since the amount in the urine corresponds to only 1.40% of the total radioactivity recovered. (Reproduced, with permission, from [127]). [5,7, H]20E to 6-7 week-old male Wistar rats.…”

Section: Pharmacokinetics After Oral Administration In Mice-more Recent Studiesmentioning

confidence: 99%

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20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases

et al. 2021

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There is growing interest in the pharmaceutical and medical applications of 20-hydroxyecdysone (20E), a polyhydroxylated steroid which naturally occurs in low but very significant amounts in invertebrates, where it has hormonal roles, and in certain plant species, where it is believed to contribute to the deterrence of invertebrate predators. Studies in vivo and in vitro have revealed beneficial effects in mammals: anabolic, hypolipidemic, anti-diabetic, anti-inflammatory, hepatoprotective, etc. The possible mode of action in mammals has been determined recently, with the main mechanism involving the activation of the Mas1 receptor, a key component of the renin–angiotensin system, which would explain many of the pleiotropic effects observed in the different animal models. Processes have been developed to produce large amounts of pharmaceutical grade 20E, and regulatory preclinical studies have assessed its lack of toxicity. The effects of 20E have been evaluated in early stage clinical trials in healthy volunteers and in patients for the treatment of neuromuscular, cardio-metabolic or respiratory diseases. The prospects and limitations of developing 20E as a drug are discussed, including the requirement for a better evaluation of its safety and pharmacological profile and for developing a production process compliant with pharmaceutical standards.

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Section: Some Drugability Calculationssupporting

confidence: 90%

Section: Pharmacokinetics After Oral Administration In Mice-more Recent Studiessupporting

confidence: 71%

“…The metabolism of radiolabelled 20E has been more extensively studied [126,127]. These studies involved 20E radiolabelled in the nucleus, so as to be able to follow sidechain cleavage.…”

Section: Pharmacokinetics After Oral Administration In Mice-more Recent Studiesmentioning

confidence: 99%

Section: Pharmacokinetics After Oral Administration In Mice-more Recent Studiesmentioning

confidence: 99%

Section: Pharmacokinetics After Oral Administration In Mice-more Recent Studiesmentioning

confidence: 99%

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20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases

et al. 2021

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A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults

Dioh

Tourette

Signore

et al. 2023

J cachexia sarcopenia muscle

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Background Sarcopenia is an age-related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20-Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study. Methods This study is a Single Ascending Dose (SAD) followed by a 14-day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen-III-amino-terminal propeptide (PIIINP), myoglobin, creatine-kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels. Results BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than doseproportionally. Mean half-life was short (2.4-4.9 h), and mean renal clearance was comparable in all doses (4.05-5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%-15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK-MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14-deoxy-20-hydroxyecdysone and 14deoxypoststerone) were identified and quantified. Conclusions BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age-related sarcopenia (SARA-INT) and Phase 3 in Covid-19 (COVA).

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Prumnopitys Andina Fruit Extract Activates Liver X Receptors after In Vitro Digestion

Jiménez‐Aspee

Pospiech

Bauer

et al. 2022

Molecular Nutrition Food Res

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Scope: 20-Hydroxyecdysone (20E) is the main phytochemical present in the fresh arils of Prumnopitys andina. 20E is reported to have anabolic effects by modulation of gene transcription by interaction with nuclear receptors. Our aim is to evaluate the in vitro bioaccessibility, transepithelial transport of 20E, and the capacity of P. andina fruit extract and 20E to activate selected mammalian nuclear receptors in transiently transfected human cells after simulated gastrointestinal digestion. Results: 20E shows good stability, solubility, and micellization after in vitro digestion. 20E is taken up by Caco-2 cells, but poorly transported through the epithelial cell membrane, possibly due to P-glycoprotein-mediated efflux. In transiently transfected HepG2 cells, the fruit extract significantly induces the signal intensity for the liver X receptor (LXR)-𝜶 and -𝜷 by 1.6 and 1.4-fold, respectively. In contrast, the treatment with 20E, irrespective of its concentration, did not change the activity of both LXR receptors. No effects are observed for the pregnane X receptor or the constitutive androstane receptor. Conclusion: Our findings show that components of the digested P. andina extract other than 20E are responsible for the effects on LXR-𝜶 and -𝜷. Our findings open new perspectives on the potential role of P. andina fruits in cholesterol metabolism and inflammatory diseases.

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Ecdysteroid metabolism in mammals: The fate of ingested 20-hydroxyecdysone in mice and rats

Cited by 8 publications

References 28 publications

20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases

20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases

A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults

Prumnopitys Andina Fruit Extract Activates Liver X Receptors after In Vitro Digestion

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