Ecdysteroid metabolism in mammals: The fate of ingested 20-hydroxyecdysone in mice and rats
Open accessAbstract
Phytoecdysteroids are molecules derived from sterol metabolism and found in many plants. They display a wide array of pharmacological effects on mammals (e.g. anabolic, anti-diabetic). Although these effects have been long established, the molecular targets involved remain to be identified. Like endogenous steroid hormones and bile acids, which are biochemically related, ingested or injected phytoecdysteroids undergo a set of reactions in mammals leading to the formation of numerous metabolites, only some of which have been so far identified, and it is presently unknown whether they represent active metabolites or inactivation products. In the large intestine, ecdysteroids undergo efficient 14-dehydroxylation. Other changes (reductions, epimerization, side-chain cleavage) are also observed, but whether these occur in the liver and/or large intestine is not known. The purpose of this study was to investigate the pharmacokinetics of 20-hydroxyecdysone (20E), the most common phytoecdysteroid, when administered to mice and rats, using, when required, tritium-labelled molecules to permit metabolic tracking. Bioavailability, the distribution of radioactivity and the kinetics of formation of metabolites were followed for 24-48 hours after ingestion and qualitative and quantitative analyses of circulating and excreted compounds were performed. In mice, the digestive tract always contains the majority of the ingested 20E. Within 30 min after ingestion, 20E reaches the large intestine, where microorganisms firstly remove the 14-hydroxyl group and reduce the 6-one. Then a very complex set of metabolites (not all of which have yet been identified) appears, which correspond to poststerone derivatives formed in the liver. We have observed that these compounds (like bile acids) undergo an entero-hepatic cycle, involving glucuronide conjugation in the liver and subsequent deconjugation in the intestine. Despite the very short half-life of ecdysteroids in mammals, this entero-hepatic cycle helps to maintain their plasma levels at values which, albeit low (≤0.2 μM), would be sufficient to evoke several pharmacological effects. Similar 20E metabolites were observed in mice and rats; they include in particular 14-deoxy-20E, poststerone and 14-deoxypoststerone and their diverse reduction products; the major products of this metabolism have been unambiguously identified. The major sites of metabolism of exogenous ecdysteroids in mammals are the large intestine and the liver. The entero-hepatic cycle contributes to the metabolism and to maintaining a low, but pharmacologically significant, concentration of ecdysteroids in the blood for ca. 24 h after ingestion. These data, together with parallel in vitro experiments provide a basis for the identification of 20E metabolite(s) possibly involved in the physiological effects associated with ecdysteroids in mammals.
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Values from urine excreted after BIO101 administration over the 0-12 h after 14 days administration with 2.38%, 3.14% and 3.01% of 350 mg qd; 350 mg bid and 450 mg bid, respectively, can be considered comparable with what was reported in rodents (1%).
“Values from urine excreted after BIO101 administration over the 0–12 h after 14 days administration with 2.38%, 3.14% and 3.01% of 350 mg qd; 350 mg bid and 450 mg bid, respectively, can be considered comparable with what was reported in rodents (1%).”
From A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults (2023) · cites this paper as [20]
Given the low oral bioavailability and the small amounts recovered from urine, it is expected that excretion proceeds mainly in the faeces, as in rodents.
“Given the low oral bioavailability and the small amounts recovered from urine, it is expected that excretion proceeds mainly in the faeces, as in rodents. 20”
From A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults (2023) · cites this paper as [20]
Post, 14dPost, 6OH14dPost and 14d20E were found as 20E metabolites in rat plasma after oral administration of BIO101 at 1000 mg/kg/day (NOAEL in rats), but their relative proportion differed compared with humans.
“Post, 14dPost, 6OH14dPost and 14d20E were found as 20E metabolites in rat plasma after oral administration of BIO101 at 1000 mg/kg/day (NOAEL in rats), but their relative proportion differed compared with humans.”
From A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults (2023) · cites this paper as [20]
In rodents, 20E metabolism occurs mainly through 14-dehydroxylation, side chain cleavage and reduction of the 6-keto group.
“In rodents, 20E metabolism occurs mainly through 14‐dehydroxylation, side chain cleavage and reduction of the 6‐keto group.”
From A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults (2023) · cites this paper as [20]
The major circulating and excreted metabolites in rodents are 14d20E, Post, 14dPost and 6αOH20E.
“The major circulating and excreted metabolites in rodents are14d20E, Post, 14dPost and 6αOH20E. 20 , 27”
From A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults (2023) · cites this paper as [20]
Concerning the other metabolites, their microbial origin is the most probable, based on (1) the high inter-individual variability of their plasma concentrations; (2) the absence of any observable in vitro metabolism by HepG2 cells or liver microsomes; (3) the observation that IV-injected 20E was recovered unchanged in rat bile.
“Concerning the other metabolites, their microbial origin is the most probable, based on (1) the high inter‐individual variability of their plasma concentrations; (2) the absence of any observable in vitro metabolism by HepG2 cells or liver microsomes (human, rats, dogs, mouse, rat, monkey; data not shown); (3) the observation that IV‐injected 20E was recovered unchanged in rat bile 20 .”
From A Phase 1 study for safety and pharmacokinetics of BIO101 (20‐hydroxyecdysone) in healthy young and older adults (2023) · cites this paper as [20]
20E is a non-toxic substance for which pharmacokinetic studies have been carried out in both rodents and humans.
“20E is a non-toxic substance for which pharmacokinetic studies have been carried out in both rodents and humans [8,9].”
From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [9]
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- Authors
- Dinan, L., Balducci, C., Guibout, L., Foucault, A.-S., Bakrim, A., Kumpun, S., Girault, J.-P., Tourette, C., Dioh, W., Dilda, P. J., Veillet, S., & Lafont, R.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Sorbonne Université (FR)
- Corresponding author
- Dinan, L.
- ORCID
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 212
- Pages
- 105896
- ISSN
- 0960-0760 (ISSN-L)
- OpenAlex
- W3145561128
- Cited by
- 23
- References
- 34
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 1 · 2023: 6 · 2022: 2 · 2021: 3
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 357 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Fonds unique interministériel
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phytochemical Studies and Bioactivities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- 20-hydroxyecdysone, phytoecdysteroids, pharmacokinetics, enterohepatic circulation, glucuronidation, hepatic metabolism, bioavailability, bile acid metabolism
- MeSH terms
- Administration, Oral, Animals, Bile, Biological Availability, Ecdysterone, Feces, Female, Gastric Mucosa, Intestinal Mucosa, Liver, Male, Mice, Inbred C57BL, Rats, Sprague-Dawley, Rats, Wistar, Glucuronides, Mice, Rats
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