Grapefruit juice and licorice increase cortisol availability in patients with Addison's disease

Abstract

Objective: Failure to mirror the diurnal cortisol profile could contribute to the impaired subjective health status in Addison's disease (AD). Some patients report benefit from the use of various nutritional compounds. The objective of this study was to investigate the impact of licorice and grapefruit juice (GFJ) on the absorption and metabolism of cortisone acetate (CA). Design: Patients (nZ17) with AD on stable CA replacement therapy were recruited from the outpatient clinic at Haukeland University Hospital, Norway. They were assessed on their ordinary CA medication and following two 3-day periods of co-administration of licorice or GFJ. Methods: Time series of glucocorticoids (GCs) in serum and saliva were obtained, and GCs in 24 h urine samples were determined. The main outcome measure was the area under the curve (AUC) for serum cortisol in the first 2.6 h after orally administered CA. Results: Compared with the ordinary treatment, the median AUC for serum cortisol increased with licorice (53 783 vs 50 882, P!0.05) and GFJ (60 661 vs 50 882, P!0.05). Median cortisol levels in serum were also elevated 2.6 h after tablet ingestion (licorice 223 vs 186 nmol/l, P!0.05; GFJ 337 vs 186 nmol/l, P!0.01). Licorice increased the median urinary cortisol/cortisone ratio (0.43 vs 0.21, P!0.00001), whereas GFJ increased the (allo-tetrahydrocortisolCtetrahydrocortisol)/tetrahydrocortisone ratio (0.55 vs 0.43, P!0.05).

Identification of Key Licorice Constituents Which Interact with Cytochrome P450: Evaluation by LC/MS/MS Cocktail Assay and Metabolic Profiling

“…Chemical structures of licorice compounds (isolated from Glycyrrhiza uralensis Fisch.). The compounds were 4-hydroxybenzoic acid (1), phloretic acid (2), liquiritin apioside (3), liquiritin (4), isoliquiritin apioside (5), isoliquiritin (6), ononin (7), 4′,7-dihydroxyflavone (8), liquiritigenin (9), licoricesaponin A3 (10), licopyranocoumarin (11), echinatin (12), naringenin (13), genistein (14), licorice-saponin G2 (15), licorice-saponin E2 (16), 3-methylkaempferol (17), davidigenin (18), glycyrrhizic acid (19), isoliquiritigenin (20), 7,4′-dihydroxy-3′-methoxyisoflavan (21), formononetin (22), glycycoumarin (23), semilicoisoflavone B (24), kumatakenin (25), licoisoflavone A (26), licoricone (27), isolicoflavonol (28), lupiwighteone (29), glycyrol (30), glyurallin A (31), licoflavonol (32), topazolin (33), glycyrin (34), gancaonin I (35), angustone A (36), isoangustone A (37), gancaonin G (38), 6,8-diprenylgenistein (39), and 18β-glycyrrhetinic acid (40). Api apinose, GluA glucuronic acid, Glc glucose, Prenyl isoprenoid.…”

“…For instance, oral intake of 7.5 g/kg licorice could increase the area under plasma concentration-time curve (AUC) of methotrexate by 127% and extend the mean residence time from 240 to 921 min (11). Licorice has also been reported to alter the pharmacokinetics of drugs like warfarin (8), cyclosporine (12), and cortisol (13). Therefore, NIH has indicated that licorice "might have moderate effect on medications changed by the liver cytochrome P450 2C9 and 3A4" (10).…”

Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure

“…Recently, partial preservation of cortisol secretion in some AD patients has been documented (27,28,29), which possibly correlates with adrenal medullary function and could partly explain the large diversity in fatigue after stress and propensity to adrenal crisis.…”

Group 4: Replacement therapy for adrenal insufficiency

“…Inhibitors of cytochrome P450 accelerate the catabolism of fludrocortisone; conversely inhibitors of cytochrome P450 such as phenytoin and phenobarbital reduce catabolism. Licorice and grapefruit juice both potentiate the mineralocorticoid action of hydrocortisone and thus should be avoided [67].…”