Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review

Abstract

Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11βHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.

Safety of jidabokuippo administration based on adverse event rate

“…Its metabolite, glycyrrhetic acid, facilitates potassium excretion and thus lowers total serum potassium. Attention should be paid to hypokalemia, myopathy, edema, and hypertension caused by pseudoaldosteronism [23]. The adverse event rate of pseudoaldosteronism in previous reports was 0.4% (four cases), while that in this study was 0.3% (three).…”

“…Homma suggested that 60 years of age and older, administration for more than 30 days, and concomitant use of drugs inducing hypokalemia were risk factors for developing pseudoaldosteronism [25]. Mantani speculated that the incidence in patients administered Glycyrrhiza 1 g/day was 1.0%, that with 2 g/day 1.7%, that with 4 g/day 3.3%, and that with 6 g/day 11.1% [23]. In this study, it occurred in elderly patients ranging from 69 to 92 years old who were administered Glycyrrhiza 1.5 g/day for 3–8 days.…”

Effect of the Japanese herbal drug rikkunshito for the treatment of malnutrition in patients with chronic heart failure

“…In fact, there was no significant change of ECW/TBW or potassium level in the whole cohort (Table 2). The dose dependency of glycyrrhiza‐induced pseudo‐aldosteronism has been reported [31]. However, the contained amount of glycyrrhiza is only 1.0 g in 7.5 g rikkunshito.…”

Pharmacokinetic Interactions of a Licorice Dietary Supplement with Cytochrome P450 Enzymes in Female Participants

“…Glycyrrhizic acid is the primary source of sweetness in licorice, but it is metabolized to glycyrrhetinic acid, which inhibits type-2 11β-hydroxysteroid dehydrogenase (Molhuysen et al, 1950). 11β-Hydroxysteroid dehydrogenase decomposes cortisol in the distal nephron, and inhibition of this enzyme can cause hypokalemia and have other effects related to mineralocorticoid receptor activity (Yoshino et al, 2021).…”

“…Consequently, the United States Food and Drug Administration (FDA) has established guidance for clinical evaluation of drug-drug pharmacokinetic interactions involving CYP enzymes (U.S. Food and Drug Administration, 2020), and similar clinical studies have been described for the evaluation of the drug-botanical pharmacokinetic interactions (Yoshino et al, 2021). The approach involves measuring the effect of the test drug or botanical dietary supplement on the pharmacokinetics of a low dose of a probe drug or a cocktail of probe drugs, each of which is metabolized by a specific CYP enzyme.…”