Enoxolone, also known as 18β-glycyrrhetinic acid or glycyrrhetinic acid, is a pentacyclic triterpenoid derived from licorice root (Glycyrrhiza glabra), a plant used for over 2,000 years across cultures for its soothing properties. Historically employed to treat digestive and respiratory ailments, the compound was eventually isolated and studied for its therapeutic potential. Enoxolone exhibits anti-inflammatory, antioxidant, and antimicrobial effects, is used topically for skin and oral inflammation, and is being explored for applications in osteoarthritis, pain relief, and the development of derivatives like carbenoxolone for gastritis and peptic ulcer treatment.
BRAND NAMES
Some of the brand names for enoxolone include Angileptol, Anzibel, Arthrodont, Dermanox, Perfluxi Cremagel, PO 12, PruClair, and it is also an ingredient in Salonpas pain relief patches in Japan and sold as Vetic in Singapore.
MECHANISM OF ACTION
Enoxolone exerts its effects by inhibiting inflammatory and apoptotic pathways, modulating the ERK1/2 signaling pathway, and interfering with purine and ATP metabolism. It reduces inflammation by lowering pro-inflammatory cytokines such as IL-17A and can suppress the production of bacterial toxins like TcdA and TcdB from Clostridioides difficile. Additionally, enoxolone promotes autophagy by increasing the expression of LC3-II and Beclin-1.
PHARMACOKINETICS
Absorption
Enoxolone is absorbed into the bloodstream mainly after glycyrrhizin is hydrolyzed by intestinal bacteria following oral administration; while glycyrrhizin itself has poor oral bioavailability, the resulting enoxolone metabolite is readily absorbed from the gut.
Distribution
Once absorbed, enoxolone is widely distributed throughout the body, accumulating in organs such as the liver and kidneys, and is also capable of crossing the blood-brain barrier.
Metabolism
Enoxolone is metabolized in the liver to form conjugates, primarily 3β-monoglucuronyl-18β-glycyrrhetinic acid, which aids in elimination, and it also inhibits enzymes involved in prostaglandin metabolism, contributing to its anti-inflammatory effects.
Excretion
Enoxolone is primarily eliminated via bile, with its glucuronide conjugates undergoing enterohepatic circulation, allowing reabsorption and a prolonged half-life, while only a small fraction (about 1.1–2.5%) is excreted in urine.
PHARMACODYNAMICS
The main pharmacodynamic effect of enoxolone (18β-glycyrrhetinic acid) is the inhibition of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme, which underlies both its anti-inflammatory properties and its potential to induce apparent mineralocorticoid excess.
ADMINISTRATION
Enoxolone can be administered orally, topically, or as part of formulated products depending on the therapeutic use. Oral forms are absorbed after hydrolysis of glycyrrhizin in the gut, while topical formulations are applied directly to the skin or oral mucosa for local anti-inflammatory effects. Dosage and frequency should follow medical guidance to ensure efficacy and minimize potential side effects.
DOSAGE AND STRENGTH
The dosage of enoxolone varies depending on the formulation, route of administration, and clinical indication. Oral doses are typically calculated based on the glycyrrhizin or enoxolone content, while topical preparations are applied as directed to affected areas. Strengths differ across products, and treatment should follow medical recommendations to achieve therapeutic effects while minimizing the risk of side effects.
DRUG INTERACTIONS
Enoxolone may interact with medications that affect electrolyte balance, such as diuretics, corticosteroids, or antihypertensives, increasing the risk of hypokalemia, hypertension, or fluid retention. It can also influence the metabolism of drugs processed by liver enzymes and may enhance the effects of anticoagulants or other medications sensitive to mineralocorticoid activity. Monitoring and dose adjustments may be necessary when used concomitantly with these agents.
FOOD INTERACTIONS
Enoxolone (glycyrrhetinic acid), a component found in licorice root, has significant food-related interactions, primarily stemming from the consumption of licorice-containing products. The primary concern is its ability to cause sodium and water retention and potassium loss, which can lead to various health issues.
CONTRAINDICATIONS
Enoxolone is contraindicated in individuals with hypertension, cardiovascular conditions (including heart failure or a history of arrhythmias), kidney disease, or hypokalemia. Its use during pregnancy and lactation should be avoided unless specifically advised by a healthcare professional.
SIDE EFFECTS
Hypertension (high blood pressure)
Hypokalemia (low potassium levels), which can cause muscle weakness, muscle pain, and in severe cases, muscular paralysis
Sodium and water retention (edema/swelling, weight gain)
Metabolic alkalosis
Suppression of the renin-angiotensin-aldosterone system
Cardiac issues, including abnormal heart rhythms (arrhythmias) and, in extreme cases, cardiac arrest, often due to severe hypokalemia
Hormonal imbalances, as enoxolone might have estrogen-like effects and can affect testosterone levels
OVER DOSE
An overdose of enoxolone (glycyrrhetinic acid, the active principle in licorice) primarily leads to a condition called pseudohyperaldosteronism, characterized by hypertension (high blood pressure), hypokalemia (low blood potassium levels), and fluid retention. In severe cases, these effects can be life-threatening.
TOXICITY
Enoxolone toxicity is mainly associated with its impact on mineralocorticoid activity, leading to sodium and water retention, potassium depletion, and elevated blood pressure, a condition known as pseudohyperaldosteronism.
