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

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

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.

Study Overview

• Status: Completed
• Conditions: Addison Disease
• Intervention / Treatment: Dietary supplement: Liquorice; Dietary supplement: Grapefruit Juice

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Bergen, Norway, 5020
    • Haukeland University Hospital, Helse-Bergen HF

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Haukeland University Hospital
• Investigators: Principal Investigator: Paal Methlie, MD, University of Bergen. Helse-Bergen HF; Principal Investigator: Kristian Løvås, MD, PhD, University of Bergen. Helse-Bergen HF.; Principal Investigator: Eystein S Husebye, Prof, MD, University of Bergen. Helse-Bergen HF.; Principal Investigator: Ernst A Lien, Prof. MD., University of Bergen

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: December 22, 2010
• First Submitted That Met QC Criteria: January 5, 2011
• First Posted (Estimate): January 6, 2011

Study Record Updates

• Last Update Posted (Estimate): January 17, 2011
• Last Update Submitted That Met QC Criteria: January 13, 2011
• Last Verified: December 1, 2010

More Information

Terms related to this study

• Keywords: Quality of Life; Pharmacokinetics; Hormone Replacement Therapy; Addison Disease; cortisone acetate
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Adrenal Gland Diseases; Adrenal Insufficiency; Addison Disease
• Other Study ID Numbers: 3.2007.2620 (REK); 17775 (NSD) (Other Identifier: Norwegian Social Science Data Services (registry for approval of data protection)); 07/5829 (SHdir) (Other Identifier: The Norwegian Directorate of Health and Social Affairs (Approval of research biobank)); 3.2007.2620 (Other Identifier: West Regional Committee of Research Ethics)