Protocol Number: 04-DK-0140

Title:

The Effects of Thyroid Hormone on Cytochrome P450 and P-Glycoprotein Activity in Thyroid Cancer Patients

Number:

04-DK-0140

Summary:

This study will examine whether and how levothyroxine (Synthroid, a synthetic thyroid hormone) affects the way the body handles other drugs. If levothyroxine does affect the metabolism of other drugs, the dose of those medications may need to be increased to enhance their action or decreased to avoid adverse reactions.

Patients 18 years of age and older with thyroid cancer who are participating in NIH protocol #77-DK-0096 and are receiving long-term suppression therapy with levothyroxine may be eligible for this study. This is not a study of thyroid cancer or of potential new drugs to treat it. Thyroid cancer patients are being studied because their treatment regimen provides an opportunity to study drug metabolism while patients are both on and off levothyroxine therapy.

Participants come to the NIH Clinical Center on two occasions: once while they are regularly taking their levothyroxine, and once while they are off the medication in preparation for their radioactive iodide diagnostic scan for the procedures outlined below. The time interval between the two clinic visits depends on whether the first visit is while the patient is on or off medication. Participants are asked to fast overnight before each visit and to abstain from certain foods and beverages for 48 to 72 hours before the visit. At each visit, patients undergo the following procedures:

- Medication history, limited physical examination, and blood draw for laboratory tests, including a test to look for genes important in eliminating medications from the body.

- Insertion of a catheter (thin plastic tube) into an arm vein for collecting blood samples.

- Shave skin biopsy (optional) to explore how proteins in the skin that metabolize and transport drugs are affected by thyroid hormone. For this procedure, the skin is cleaned, numbed with medicine, and a small sample of the top layer is removed with a razor blade. The wound heals in 2 to 3 days.

- Medication dosing. Participants take all of the following substances by mouth at the same time: 1) 200 mg of caffeine, a compound commonly found in chocolate, soda/pop, coffee, tea and non-prescription products to prevent sleep; 2) 30 mg of dextromethorphan, a non-prescription cough suppressant; 3) 40 mg of omeprazole, a prescription drug for heartburn and stomach ulcers; 4) 8 mg of midazolam, a prescription drug used to cause relaxation and drowsiness; and 5) 120 mg of fexofenadine, a non-sedating prescription antihistamine used to treat allergies.

- Blood and urine sampling. Fifteen blood samples of about 5 mL (1 teaspoon) each are collected through the catheter and urine is collected over the next 24 hours to determine what happens to the test drugs in the body.

Participants may resume their normal diet 4 hours after taking the study medications.

Sponsoring Institute:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

1. Subject has signed the informed consent document;

2. Subject is greater than or equal to 18 years of age;

3. Subjects diagnosed with thyroid cancer participating in protocol 77DK0096;

4. Subjects receiving THST with levothyroxine;

5. Serum TSH less than 0.4 mIU/L while on THST, and more than 20 mIU/L while off THST.

EXCLUSION CRITERIA:

Subject is pregnant, currently breast-feeding, practicing birth control with hormonal contraceptives, or is on hormone replacement therapy (HRT).

Subject is a smoker.

Subject has a confounding medical illness (es) that in the judgement of the investigators would pose an added risk for the subject (e.g. severe respiratory disease).

Subject has a history of substance abuse within the past 5 years or drug or alcohol use, that may affect enzyme levels and function.

Caffeine or caffeine-containing beverages and chocolate bars consumption within 48 hours of scheduled caffeine administration for CYP1A2 phenotyping; scheduled omeprazole administration during or within 14 days of the study; scheduled dextromethorphan administration during or within 30 days of study; scheduled fexofenadine administration during or within 7 days of the study.

AST or ALT greater than or equal to 2 times the upper normal reference limit.

Concurrent administration of known CYP and/or P-gp inducers (barbiturates, phenytoin, carbamazepine, rifampicin) and inhibitors (amiodarone, atorvastatin, chloroquine, cimetidine, co-trimoxazole, cyclosporine, diltazem, erythromycin, fluoxetine fluvoxamine, isoniazid, itrakonazole, ketokonazole, metronidazole, mexiletine, nefazadone, norfloxacin, verapamil) or use of any alternative/complementary therapies for at least 30 days prior to study or during the study. Non-herbal vitamin and mineral preparations will be allowed.

Inability to obtain venous access for sample collection, or basal hemoglobin of equal or less than 10 g/dl.

Patients receiving scheduled therapy with alprazolam, triazolam, clonazepam, diazepam, lorazepam, oxazepam, temazepam or chlorodiazepoxide, during or within 30 days of study.

Patients consuming grapefruit products (juice or the fresh fruit), apple and orange juice during or within 72 hrs of study.

History of intolerance to caffiene, omeprazole, dextromethorphan, midazolam or fexofenadine.

The presence of persistent diarrhea or malabsorption syndromes that would interfere with the patient's ability to adequately absorb drugs; and/or

Patients receiving monoamine oxidase inhibitors (MAOIs) such as phenelzine, tranylcypromine, and isocarboxazid.

Patients with a history of cheloids formation.

Special Instructions: Currently Not Provided

Keywords:

Pharmacokinetics

Drug Metabolism

Levothyroxine

Hypothyroidism

Hyperthyroidism

Drug Interactions

Cytochrome P450

P-Glycoprotein

Drug Transport Proteins

Thyroid Hormone

Recruitment Keywords:

Thyroid Cancer

Conditions:

Thyroid Cancer

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Meisel C, Gerloff T, Kirchheiner J, Mrozikiewicz PM, Niewinski P, Brockmoller J, Roots I. Implications of pharmacogenetics for individualizing drug treatment and for study design. J Mol Med. 2003 Mar;81(3):154-67. Epub 2003 Mar 15. PMID: 12682724

Nolan SR, Self TH, Norwood JM. Interaction between rifampin and levothyroxine. South Med J. 1999 May;92(5):529-31. PMID: 10342905

Blackshear JL, Schultz AL, Napier JS, Stuart DD. Thyroxine replacement requirements in hypothyroid patients receiving phenytoin. Ann Intern Med. 1983 Sep;99(3):341-2. PMID: 6614682

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