Effects and Interactions of Liquorice and Grapefruit on Glucocorticoid Replacement Therapy in Addison's Disease

Study Overview
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Brief Summary
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Addison's disease is a rare disease, wherein the adrenals can not produce sufficient steroid hormones (cortisol and aldosterone). Patients with Addison's disease report impaired subjective health status, and they have increased all-cause mortality. Conventional therapy is by oral replacement of glucocorticoid and mineralocorticoid hormones, but this strategy imperfectly mimic the diurnal cortisol variations, and render the patients both over- and under-treated. Anecdotally, some patients with adrenal insufficiency may benefit from the use of various nutritional compounds. We hypothesised that liquorice and grapefruit altered the metabolism and absorption of cortisone acetate.

Detailed Description
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In the present study, cortisone acetate absorption and metabolism are assessed in subjects with Addison's disease on three occasions. On the first occasion, the subjects are on their regular diet, but avoid ingestion of grapefruit and liquorice. At the end of the baseline assessment the order of the nutritional compounds (liquorice-grapefruit juice or grapefruit juice-liquorice) to be investigated in the next two assessments are randomised. On the two next occasions, the absorption and metabolism of cortisone acetate is studied when study subjects consume liquorice and grapefruit juice. Between the use of grapefruit and liquorice there is a wash out period of at least 3 weeks. For studies on liquorice effects, the subjects ingest 24-gram liquorice per day (equivalent of 150-mg glycyrrhizinic acid per day). For studies on grapefruit juice effects, subjects drink 200-ml grapefruit juice three times a day for three days. They maintain their regular medication and usual diet. Time-series of cortisol and cortisone are obtained in serum and saliva samples on the third day of liquorice/grapefruit juice use. 24-hour urine is also collected. Measurements of cortisol and metabolites in serum and saliva are used to calculate pharmacokinetical parameters. The measurements from samples obtained when using the investigated nutritional compounds are compared to the baseline assessment in each subject. Metabolites in 24-hour urine are compared similarly to investigate changes in urinary excretion, and to estimate the activity of enzymes involved in the metabolism of cortisol (5alfa-reductase, 5beta-reductase, cytochrome P450 3A4 system, 11-beta hydroxysteroid dehydrogenase).

Official Title
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Use of Liquorice and Grapefruit in Patients With Addison's Disease

Conditions
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Addison Disease

Intervention / Treatment
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* Dietary Supplement: Liquorice
* Dietary Supplement: Grapefruit Juice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Verified diagnosis of adrenal insufficiency (Addison's disease) Stable cortisone acetate replacement therapy Written informed consent Exclusion Criteria: Malignant disease Pharmacological treatment with other glucocorticoids Pregnancy Current minor disease (ie the flu) Major disease or accident requiring hospitalization the last three months Use of grapefruit juice or liquorice the last two weeks before study start Blood pressure above 150mmHg systolic or 90 mmHg diastolic.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liquorice<br>Liquorice eq to 150 mg glycyrrhizinic acid. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion. | Dietary Supplement: Liquorice<br>* 24 gram liquorice eq. to 150 mg glycyrrhizinic acid, taken orally, for three days.<br>|
| Active Comparator: Grapefruit juice<br>200 ml pink grapefruit juice three times a day. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion. | Dietary Supplement: Grapefruit Juice<br>* 200 ml pink grapefruit juice three times a day, taken orally, for three days.<br>|
| No Intervention: Baseline<br>Baseline assessment without intake of liquorice or grapefruit juice | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC Serum Cortisol - Levels of cortisol in serum during the first 2.6 hours after oral administration of cortisone acetate. | The area under the curve (AUC) of cortisol is calculated based on serum time-series sampling (every 20 minutes for 2.6 h after oral administration of cortisone acetate). The AUCs obtained during liquorice and grapefruit juice intakes are compared to the baseline assessment (without these nutritional compounds). All other pharmacokinetic properties (primary and secondary outcome measures) are compared analogously. | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Cortisol levels at the end of time-series sampling (t=160min) | At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Serum Cortisone levels at the end of time-series sampling (t=160min) | At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Saliva Cortisol levels at the end of time-series sampling (t=160min) | At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Saliva Cortisone levels at the end of time-series sampling (t=160min) | At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Time of maximum concentration of serum Cortisol | Based on time-series sampling at each of the three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Time of maximum concentration of serum Cortisone | Based on time-series sampling at each of the three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Time of maximum concentration of Saliva Cortisol | Based on time-series sampling at each of the three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Time of maximum concentration of Saliva Cortisone | Based on time-series sampling at each of the three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Half life of serum cortisol | Based on time-series sampling at each of the three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Half life of serum cortisone | Based on time-series sampling at each of the three assessments | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Urinary aTHF/THF-ratio | Measured in 24h urine obtained at the three assessments. aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| AUC Serum Cortisone | Similar to primary outcome Serum AUC Cortisol | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE) | 24-hour urine collected on each of the three assessments aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone, 6OHF = 6beta-hydroxycortisol | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Urinary ratio (aTHF+THF)/THE | Assessed in 24h urine obtained at the three assessments (baseline, after liquorice and after grapefruit juice). It is an index of 5-reductase activity. 24-hour urine collected on each of the three assessments aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Urinary Ratio Cortisol/6beta-OH-Cortisol | Assess the enzymatic activity of CYP3A4 by the index urinary cortisol/6beta-oh cortisol ratio obtained at the three assessments (baseline, after liquorice and after grapefruit juice. 6OHF = 6beta-hydroxycortisol | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE) | 24-hour urine collected on each of the three assessments 24-hour urine collected on each of the three assessments aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone, 6OHF = 6beta-hydroxycortisol | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| AUC Saliva cortisone | Similar to primary outcome Saliva AUC Cortisol, but for cortisone. | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| AUC Serum Cortisone | Similar to primary outcome Serum AUC Cortisol, but for cortisone. | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 
| AUC Saliva Cortisol | Similar to AUC Serum Cortisol, but measurements are on saliva. | Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Addison Disease, Pharmacokinetics, Hormone Replacement Therapy, cortisone acetate, Quality of Life