Drugs That May Cause Protein-Binding Site Replacement And Drugs That May Either Increase Or Decrease Serum TBG-Concentration

Levothyroxine has a narrow therapeutic index and being a drug that is administered in chronic form; there is a high risk of its interaction with different drugs that could be simultaneous administration with it when it is under use for the treatment of hypothyroidism. Levothyroxine in different steps of its pharmacokinetic could interact with various drugs. ¹⁾http://www.academicjournals.org/article/article1380787433_Pérez%20et%20al.pdf

Because thyroid hormone is highly protein bound, medical conditions that alter the amount of binding hormones and drugs that compete for binding may change the amount of available free thyroid hormone. The thyroid replacement dosage must be changed in response to both alterations in binding status ²⁾http://www.academicjournals.org/article/article1380787433_Pérez%20et%20al.pdf and alterations in amounts of transport proteins.

I. DRUGS THAT MAY EITHER INCREASE OR DECREASE SERUM TBG CONCENTRATION

 

The thyroid hormones (THs)—thyroxine (T4) and 3,5,3’-triiodothyronine T3—circulate in blood by reversibly binding to carrier proteins. The three main proteins that carry the majority (>95%) of THs are thyroxine-binding globulin (TBG), transthyretin (TTR, or prealbumin), and albumin. A minor proportion of the THs is bound on serum lipoproteins ³⁾emedicine.medscape.com/article/125764-overview.

Binding to transport proteins helps protect the hormone from premature metabolism and excretion, prolongs its half-life in the circulation and allows the thyroid hormone to reach its site of action ⁴⁾Leon Shargel at al. Comprehensive Pharmacy Review for NAPLEX. 2010; page 1200. Approximately 99.95% of the circulating thyroid hormones are bound to the plasma proteins. Only 0.02% of T4 and 0.3% of T3 circulate in the free form, but this small, unbound fraction is responsible for the biological activity of circulating thyroid hormones ⁵⁾press.endocrine.org/doi/full/10.1210/jc.2002-021869.

Thyroxine-binding globulin (TBG) has the highest affinity for T4 and T3, but it is present in the lowest concentration. Despite its low concentration, TBG carries the majority of T4 and T3 in the blood ⁶⁾en.m.wikipedia.org/wiki/Thyroxine-binding_globulin. Since TBG binds 75% of serum T4 and T3, quantitative and qualitative abnormalities of this protein have most profound effects on the total iodothyronine levels in serum (total T4 and T3) ⁷⁾www.thyroidmanager.org/chapter/thyroid-hormone-serum-transport-proteins-2/. Alterations in the total concentrations of T4 and T3 (bound and free THs) may produce a misleading high or low test results in Serum total thyroxine (TT4) and Serum total triiodothyronine (TT3) tests ⁸⁾Leon Shargel at al. Comprehensive Pharmacy Review for NAPLEX. 2010; page 1201. Furthermore, quantitative and qualitative abnormalities of this protein in hypothyroid patients may require changes in the thyroid replacement dosage.

1. Drugs that may increase serum TBG concentration:
   estrogen-containing oral contraceptives, estrogen replacement therapy (oral), SERMs: tamoxifen, raloxifen (Evista), droloxifen, heroin/methadone (Dolophine), 5-fluorouracil (Adrucil), mitotane (Lysodren), clofibrate
2. Drugs that may decrease serum TBG concentration:
   anabolic steroids, asparaginase (Elspar), danazol (Danocrine), glucocorticoids, slow-release nicotinic acid

Elevated TBG levels are associated with influences such as pregnancy, genetic predisposition, oral estrogen therapy, SERMs, and other drugs increasing serum TBG concentration. TBG levels can decrease with androgenic or anabolic steroids, glucocorticoids, danazol, hypoproteinemic states, liver disease, nephrotic syndrome, and congenital TBG variants. Normally, the thyroid adjusts to changing concentrations of TBG by producing more or less thyroid hormone to maintain a constant level of metabolically important free hormone ⁹⁾www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9263. For example, the rise in TBG during oral estrogen administration is paralleled by a T4 increase to maintain a physiological concentration of free T4 ¹⁰⁾www.eje-online.org/content/155/1/11.full.pdf. However hypothyroid patients may not be able to compensate for this interaction and may require an adjustment in the thyroid replacement therapy.

1) MEDICATIONS THAT INCREASE TBG

 

ESTROGEN THERAPY AND SERMs

Oral estrogen administration (elevated levels of estrogen) increases thyroxine binding globulin (TBG) concentrations ¹¹⁾www.eje-online.org/content/155/1/11.full.pdf. The mechanism for this increase in TBG involves both an estrogen-induced increase in hepatic synthesis of TBG (TBG is synthesized in the liver) and an estrogen-induced increase in sialylation, which increases the half-life of TBG ¹²⁾http://clinchem.org/content/45/12/2250.long. The resulting increased number of unsaturated thyroxine-binding sites (TBG) bind with free thyroxine, causing an increase in bound thyroxine and lowering of the free thyroxine level. The pituitary is stimulated by the decreased free thyroxine level to secrete thyrotropic hormone (TSH). The thyroid gland, in turn, is stimulated by the TSH to secrete thyroxine, causing the free thyroxine to return to a normal concentration ¹³⁾www.google.com/patents/US3799740. The net effect of elevated TBG synthesis is to force a new equilibrium between free and bound thyroid hormones and thus a significant increase in total T4 and T3 levels ¹⁴⁾www.vivo.colostate.edu/hbooks/pathphys/endocrine/thyroid/thyroid_preg.html. The increase in TBG concentration occurs within 2 weeks of estrogen use, and a new thyroid hormone state is achieved after 4-8 weeks. Maintaining euthyroidism and a normal serum TSH level during this time depends on the ability of the thyroid to transiently increase T4 secretion. (book) However, hypothyroid patients may not be able to compensate for this interaction ¹⁵⁾Jae Y. Choe. Drug Actions and Interactions. 2011; page 621. Therefore, the T4 substitution dose in women with primary hypothyroidism, characterized by impaired endogenous T4 production, must be increased when oral estrogens are administered ¹⁶⁾www.eje-online.org/content/155/1/11.full.pdf.

Commonly used doses of estrogen, such as ethinyl estradiol (20-30 ug daily) found in oral contraceptive pills, or conjugated estrogen (0.625 mg) cause up to a 50% increase in TBG concentration, which results in an increase in serum total T4 of up to 35%, and lesser increases of serum total T3 ¹⁷⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 256.

The effect of sex hormone therapy on thyroid function depends on the route of administration. Transdermal estrogens or testosterone therapy do not raise serum TBG and therefore do not alter the fT4 level, because transdermal sex hormones do not have a hepatic first-pass effect in contrast to oral sex hormones. Thus the transdermal route is preferable in women receiving thyroid-hormone replacement ¹⁸⁾www.njmonline.nl/getpdf.php?t=a&id=10000331. Progesterone therapy, used independently or in concert with estrogen therapy, has no independent effect on TBG concentrations ¹⁹⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 256. Thus contraceptive pills containing just progesterone are other preferable choice for women receiving thyroid-hormone replacement.

SERMs, selective estrogen receptor modulators, including tamoxifene, droloxifene, and raloxifene, have been shown to reduce risks for breast cancer, postmenopausal osteoporosis, and serious cardiovascular disease. This class of medicines has a weak agonist effect on the liver, and thus increases TBG concentrations more modestly than oral estrogen therapy. Tamoxifen induces TBG and serum total T4 level increases, while raloxifene has been observed to cause less significant changes in both TBG and serum total T4. Droloxifene, a SERM structurally similar to tamoxifen, has been shown to increase serum TSH and TBG concentrations, but does not alter free T4 index values in postmenopausal women ²⁰⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 256. No data of alterations in fT4 due to tamoxifen are known in patients with hypothyroidism. But it can be assumed that fT4 levels would change in substituted hypothyroidism ²¹⁾www.njmonline.nl/getpdf.php?t=a&id=10000331.

Furthermore, an increase in the estrogen leads to a situation which produces distorted results with the established T3 uptake and serum T4 tests. When there is an elevation of estrogen level, as during pregnancy or estrogen medication, the clinical evaluation of thyroid activity obtained from T3 uptake determinations would indicate an increase in unsaturated TBG binding sites and, therefore, hypothyroidism. Conversely, T4 determinations would indicate hyperthyroidism. However, the true clinical status under these conditions, euthyroidism, is evidenced by the normal level of free thyroxine. Thus, in this case neither the T3 uptake nor the serum T4 test result alone is adequate for correct clinical assessment, even though each test result accurately reflects the value of the variable measured ²²⁾www.google.com/patents/US3799740. It’s important that women tell their physicians that they are taking drugs containing estrogens (birth control pills, SERMs).

Furhtermore, hypothyroid women taking thyroid hormone replacement should have a repeat TSH test between 10-12 weeks after initiation of estrogen therapy ²³⁾www.mythyroid.com/drugs.html.

HEROIN AND METHADONE

Long-term heroin and methadone use have been associated with increased TBG concentrations. It is difficult to determine if the alteration of TBG is due to a specific of the narcotic, or from the coexistent liver dysfunction present in many of these patients. The free T4 index is normal in the majority of these patients. Cocaine has not been shown to have a similar effect ²⁴⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 256.

OTHER MEDICATIONS THAT INCREASE TBG

Mitotane, used as a long-term therapy in patients with adrenocortical carcinoma, has been shown to increase multiple hormone-binding globulins including TBG. This increase was reversed 1 year after mitotane was discontinued ²⁵⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 257.

5-Fluorouracil, used weekly to treat breast cancer, has been noted to cause increased total serum T4 and T3 levels in the setting of unchanged serum free T4 levels and serum TSH levels. This change is hypothesized to occur due to TBG increases. Clofibrate has similarly been noted to increase serum TBG concentrations ²⁶⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 257.

2) MEDICATIONS THAT DECREASE TBG

 

ANDROGENS

Opposite to estrogen, and SERMs, androgen administration in women decreases TBG concentrations and requires reduction of T4 substitution in patients with primary hypothyroidism to avoid thyrotoxicosis ²⁷⁾www.eje-online.org/content/155/1/11.full.pdf.

Researchers Baha and Arafah studied two groups of women with breast cancer: women with normal thyroid function and hypothyroid women who were adequately substituted with levothyroxine replacement. Both groups were treated with the oral androgen, fluoxymesterone. Serum TBG and total T4 decreased significantly in both groups within four and two weeks, respectively. In the control group fT4 levels remained unchanged and TSH decreased slightly. In the hypothyroid group on levothyroxine replacement fT4 levels increased and TSH decreased within two weeks. These biochemical changes were associated with complaints of tachycardia, hyperhydrosis and insomnia. The difference in fT4 and TSH between the control groups and the women on thyroxine is explained by the notion that subjects on levothyroxine replacement are not able to adjust their serum fT4 concentration via changes in the TSH secretion. For example, administration of androgens will decrease TBG, in all likelihood due to a decrease of glycosylation of TBG and thereby an increase in the clearance of TBG. According to the law of mass action, the reduction in TBG will increase the free fraction of circulating thyroxine (fT4), followed by a decrease in TSH secretion. Under physiological conditions the lower TSH secretion will reduce thyroxine secretion by the thyroid gland, and the equilibrium between bound and fT4 in the circulation is restored under normalisation of serum fT4. In hypothyroid patients on a fixed dose of exogenous thyroxine the adaptation to changes in serum TBG via the negative feedback of thyroid hormones on the pituitary is failing ²⁸⁾www.njmonline.nl/getpdf.php?t=a&id=10000331.

Thyroid hormone doses had to be reduced by between 25 and 50% to maintain euthyroidism. After discontinuation of the androgens, the TSH levels increased and fT4 levels decreased when patients continued on the same thyroxine dose. TBG levels returned to normal after eight to ten weeks after therapy was discontinued ²⁹⁾www.njmonline.nl/getpdf.php?t=a&id=10000331.

OTHER MEDICATIONS THAT DECREASE SERUM TBG

Nicotinic acid, used for treatment of hypercholesterolemia, has been noted to decrease serum TBG concentrations by 25%. Decreases in serum total T4 are smaller, and no changes have been described in serum TSH or free thyroid hormone levels ³⁰⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 257.

L-asparaginase, an antineoplastic therapeutic, has also been associated with an acute deficiency of TBG ³¹⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 258.

II. DRUGS THAT MAY CAUSE PROTEIN-BINDING SITE DISPLACEMENT

 

IN HEALTHY SUBJECTS, circulating T4 and T3 are tightly bound to serum proteins ³²⁾press.endocrine.org/doi/full/10.1210/jc.2002-021869.

Various medications displace thyroid hormones from protein-binding sites, inducing transient increases in free hormone concentrations and suppression of TSH levels ³³⁾press.endocrine.org/doi/full/10.1210/jc.2002-021869, but after continued administration, free T4 and TSH normalize, and serum total T4 will decrease. Typically, this effect is seen when the offending medications are used in high doses ³⁴⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 258.

Furosemide (>80 mg IV); heparin; hydantoins; non-steroidal anti-inflammatory drugs (fenamates, phenylbutazone); salicylates (>2 g/day) ³⁵⁾lifeinthefastlane.com/book/critical-care-drugs/thyroxine/:

High doses of furosemide, fenclofenac, and salicylate act as competitive inhibitors of T4 binding to TBG and some of them also to thransthyretin, and albumin, thereby raising serum FT4 ³⁶⁾Lewis E. Braverman, David Cooper. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 2012; page 210 due to drug displacement of T4 ³⁷⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 258; subsequently TSH secretion is inhibited, and serum FT4 returns to normal values. Although total T4 are decreased. The decrease in serum total T4 is caused to a large extent by a fall in T4 bound to serum proteins ³⁸⁾Lewis E. Braverman, David Cooper. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 2012; page 210.

For example, an initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. According to lowered total-T4 levels patients seem to be hypothyroid, but their free T4 levels are within normal range and patients are euthyroid. These drug-induced changes can lead to inappropriate diagnostic and therapeutic decisions ³⁹⁾press.endocrine.org/doi/full/10.1210/jc.2002-021869. The time interval between doses of these drugs and blood sampling should be considered in result interpretation.

It is important to note that both furosemide and aspirin bind T4 sites on transport proteins with affinities several orders of magnitude less than of T4 ⁴⁰⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 258.

SALICYLATES ( >2 g/day)

Salicylates, nonsteroidal antiinflammatory medicines (NSAIDs), inhibit T4 and T3 binding to both TBG and transthyretin when administered in doses greater than 2 g/day. Similarly, the NSAID salsalate inhibits binding of these thyroid hormones to TBG alone, resulting in decreases of serum total T4 (up to 30%) and total T3 concentrations ⁴¹⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 258. Faber et al. reported that a single dose of oral salicylate given to healthy volunteers increased free T₄ and decreased TSH within 30 min. Wang et al. documented decreases in total T₄ and T₃ that were maximal at 4 h and decreased TSH levels that were maximal at 8 h. McConnell reported decreased total T₄, total T₃, and TSH in healthy subjects within 24 h of starting salsalate 1500 mg twice daily, effects that persisted for 3 d ⁴²⁾press.endocrine.org/doi/full/10.1210/jc.2002-021869. While the above studies have involved high dose, long-term use, effects on thyroid function tests have also been observed after shorter courses of therapy ⁴³⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 258. In those studies, total T₄ and/or total T₃ were still decreased compared with baseline in subjects given 1 wk of salsalate or aspirin, although TSH was unchanged. In subjects who receive salicylates for longer than 1 wk, there are case reports of patients with low total T₄, although free thyroid hormone and TSH are reported to be normal . Although studies mentioned above documented significant changes in various thyroid hormone measurements during administration of some of the NSAIDs, a more relevant clinical question may be how often thyroid hormone measurements fall outside the laboratory normal range in patients receiving these agents. During short-term administration of aspirin or salsalate, total thyroid hormone measurements below the normal range were so common as to be expected in the majority of healthy subjects. Aspirin and salsalate also affect the accuracy of free thyroid hormone measurements, but fewer free hormone values were below the normal range ⁴⁴⁾press.endocrine.org/doi/full/10.1210/jc.2002-021869.

According to information mentioned above, high doses of salicylates (e.g., high doses of aspirin) may affect thyroid hormone levels in the blood. Thus, the time interval between doses of oral salicylates and blood sampling should be considered in result interpretation. Salicylates (e.g.aspirin) should be avoided to relieve the distress of profound pyrexia during the thyroid storm as they are associated with displacement of thyroid hormone binding from thyroid binding globulin TBG. However, antipyretics can be administered to reduce profound pyrexia ⁴⁵⁾http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475282/.

Low-dose aspirin should be continued if prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention (usually at dosages of 81-325 milligrams per day) ⁴⁶⁾www.webmd.com/drugs/2/drug-4054/levothyroxine-inj/details#interactions. At low concentrations, aspirin is unlikely to affect thyroid hormone levels and hypothyroid patients taking both exogenous levothyroxine and low doses of salicylates do not have to adjust their dosage of levothyroxine.

NSAID

Cremoncini et al. reported that 12 d of flurbiprofen administration did not change total T₄ or total T₃ in healthy subjects. Samuels et. al found that total or free thyroid hormone, TSH, and TRH responses were not altered after acute or 1-wk administration of high therapeutic doses of ibuprofen, naproxen, and indomethacin. This indicates that these three NSAIDs were not disruptive of normal thyroid hormone homeostasis and is consistent with the hypothesis that these agents are weaker inhibitors of thyroid hormone binding ⁴⁷⁾press.endocrine.org/doi/full/10.1210/jc.2002-021869.

FUROSEMIDE

Furosemid, a commonly used diuretic, has also been shown to inhibit T4 binding when used in doses higher than 80-100 mg daily. This effect is seen more commonly with intravenous than with oral doses ⁴⁸⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 258. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower total T4 and T3 levels. Various ligands inhibited T4 binding to serum proteins in the following relative molar relationship: T4, 1; furosemide, 1.5 X 10(3); fenclofenac, 2 X 10(4); mefenamic acid. 2.5 X 10(4); diphenylhydantoin, 4 X 10[4); ethacrynic acid, 10(5); heparin 5 X 10(5); 2-hydroxybenzoylglycine, 10(6); and sodium salicylate, 1.5 X 10(6). The drug is much more potent on a molar basis than other drug inhibitors of T4 binding, but at normal therapeutic concentrations, furosemide is unlikely to decrease serum T4 or T3. However, high doses, diminished renal clearance, hypoalbuminemia, and low TBG accentuate its T4- and T3-lowering effect. Hence, furosemide should be considered a possible cause of low thyroid hormone levels in patients with critical illness ⁴⁹⁾www.ncbi.nlm.nih.gov/m/pubmed/2579968/.

The difficulty in assessing thyroid status in severe illness is well known, and this difficulty can be complicated by treatment with drugs such as furosemide ⁵⁰⁾Surks M, Chopra I, Mariash C, Nicoloff J, Solomon D. American Thyroid Association guidelines for use of laboratory tests in thyroid disorders. JAMA 1990;263:1529 –32. Further, in sera with subnormal albumin and TBG levels (hypoalbuminemia and low TBG) displacement occurred at lower drug concentrations ⁵¹⁾www.ncbi.nlm.nih.gov/m/pubmed/2579968/.

The interference of furosemide with free thyroxine assays should further discourage sampling for thyroid tests from intravenous sites where furosemide has been administered, because contamination of the sample by even small volumes of furosemide significantly affected thyroxine results. This concern may apply to interference from other drugs (e.g., salicylates and fenclofenac) as well as to other assays (e.g., free triiodothyronine).

Because oral furosemide may influence measurement of the free thyroxine index ⁵²⁾www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9263, the time interval between doses of oral furosemide and blood sampling should be considered in result interpretation ⁵³⁾clinchem.org/content/45/12/2250.long.

HEPARIN

Heparin is a weak inhibitor of T4 binding to TBG. Its action is indirect via activation of serum lipoprotein lipase that breaks down triglycerides into non-esterified fatty acids (NEFA) and glycerol in vitro. Addition of NEFA to human serum increases the free T4 fraction by inhibiting the binding of T4 to albumin, but only if the molar ratio of NEFA to albumin is higher than 5:1, a value rarely reached even in critically ill patients ⁵⁴⁾Lewis E. Braverman, Robert D. Utiger. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 2005; page 814. Large doses of either subcutaneous or intravenous heparin, both fractionated and unfractionated, have been shown to increase plasma and decrease tissue concentrations of T4 in vitro, but have not been associated with clinical thyrotoxicosis. A similar effect has been noted when serum total and free T4 are measured shortly after an intravenous injection of 2,000 U of enoxaparin ⁵⁵⁾Gregory A. Brent. Thyroid Function Testing. 2010; page 258.