Thyroid Disorders
Read Time: 12 mins

A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism

Copy Link
Published Online: Apr 19th 2013 European Endocrinology, 2013;9(1):40-47 DOI:
Authors: Philippe Colucci, Corinne Seng Yue, Murray Ducharme, Salvatore Benvenga
Quick Links:
Article Information

Thyroxine hormone has been recognised since the early part of the nineteenth century and levothyroxine has been available since the mid-nineteenth century as a replacement for deficient thyroid hormones. While levothyroxine remains the staple treatment for hypothyroidism even to this day, its optimal use can be challenging. As is often the case with older drugs, the pharmacokinetics of levothyroxine is often under-appreciated or misunderstood and many factors influence the optimal dosing of levothyroxine. This article will review the pharmacokinetics of levothyroxine in the treatment of hypothyroidism and highlight major concepts that should aid both clinicians and researchers.


Pharmacokinetics; drugs formulations; levothyroxine; intestinal absorption; interactions between drugs; hypothyroidism


Role of the Thyroid Hormones

Role of the Thyroid Hormones
Thyroid hormones play a vital role in the human body and, as such, the absence of such hormones requires treatment. Generally, levothyroxine is used to treat thyroid hormone deficiency, and after a brief review of thyroid hormone physiology, this article will highlight what is known about the pharmacokinetics (PKs) of levothyroxine, as well as describe factors that can influence its PKs. The thyroid gland is responsible for the synthesis, storage and release of metabolic hormones including iodinecontaining thyroxine (T4) and triiodothyroxine (T3). These hormones are crucial in the regulation of many metabolic processes and are vital for normal growth and development.1 They are also involved in calorigenic, cardiovascular and metabolic effects. The hormones exert their effects presumably by activating gene transcription of messenger RNA and proteins. To do so, they enter the cell nucleus and bind to DNA-bound thyroid receptors, which regulate gene transcription.1,2

T4 and T3 Production and Feedback Loop Mechanism
Normally, the hormones secreted by the thyroid are regulated by the hypothalamic–pituitary–thyroid (HPT) axis through a negative feedback system. Low levels of circulating T4 and T3 initiate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroidstimulating hormones (TSH) from the pituitary. On interaction with its specific receptor, TSH stimulates the thyroid follicular cells to synthesise T4 and T3 and release them into the bloodstream. When circulating levels of T4 and T3 increase, they inhibit the release of TRH and TSH (i.e. negative feedback mechanism) thereby decreasing their own production.1–4 The predominant hormone produced by the thyroid gland is T4, with approximately 70–90 mcg of T4 and 15–30 mcg of T3 produced daily.1,5 The production of the T3 hormone by the thyroid gland is insufficient to meet the daily requirements of the organs in the body. Therefore, approximately 80 % of the body’s required T3 comes from peripheral conversion of T4 to T3.4,6 Although both T4 and T3 are active, T3 is more active as thyroid receptors within the cell nucleus have a 10-fold greater affinity for T3.2,4

Indication and Dosage
Levothyroxine is a synthetic T4 hormone that is biochemically and physiologically indistinguishable from the natural one, and it is administered when the body is deficient in the natural hormone.7 Oral administration of levothyroxine is thus indicated for acquired primary (thyroidal), secondary (pituitary) and tertiary (hypothalamic) hypothyroidism.8 It is also used to treat euthyroid goiters including thyroid nodules, subacute or chronic lymphocytic thyroiditis, multinodular goiter or for thyroid cancer patients who have undergone thyroidectomy, and as an adjunct to surgery and radioiodine therapy.1

For an average adult under the age of 50, the typical levothyroxine sodium dose is approximately 1.7 mcg/kg/day, which is equivalent to approximately 100–125 mcg/day. Older patients or patients with cardiac disease may require less levothyroxine and doses should be titrated at intervals of 4–6 weeks. Newborns, infants and adolescents require doses greater than 1.7 mcg/kg/day.The guidelines that were recently released by the American Association of Clinical Endocrinologists and American Thyroid Association task force on hypothyroidism in adults, in addition to diagnosis, include suggestions of therapy.9

Literature Search Method
A literature review was conducted in PubMed, Embase (1974 to week 47 of 2012) and Medline (1946 to third week of November 2012) using the terms ‘levothyroxine’ and ‘pharmacokinetics’. The searches in Pubmed and Embase/Medline returned 1217 and 147 publications, respectively.

Pharmacokinetic Properties
Major characteristics of levothyroxine PKs are summarised in Table 1 and are described in more detail below.

Absorption and Bioavailability
Levothyroxine is mainly absorbed in the small intestine, more specifically through the duodenum, jejunum and ileum.10,11 Very little is absorbed in the stomach. Consequently, patients with shorter small intestines (bowel resection) have reduced absorption and require higher levothyroxine doses.12 The time to maximum concentration (Tmax) occurs at approximately 2 hours in euthyroid volunteers while it is delayed to approximately 3 hours in hypothyroid patients.13 Food also delays Tmax.13,14

The bioavailability of levothyroxine is approximately 60–80 % in euthyroid volunteers.14–16 It may be slightly higher in hypothyroid and hyperthyroid patients,15,16 and is decreased in the presence of food from 79 % under fasted conditions to 64 % under fed conditions for a 100 mcg dose.14

The absorption of levothyroxine appears to be influenced by gastric pH.17,18 Centanni et al. demonstrated that in euthyroid patients suffering from nontoxic multinodular goiter, impaired gastric acid secretion or the use of omeprazole was associated with increased dosing requirements in order to adequately suppress TSH.17 Similarly, Sachmechi and colleagues showed that chronic lansoprazole use in hypothyroid patients also resulted in increased levothyroxine dose requirements to maintain targeted TSH levels.18

Volume of Distribution
Levothyroxine has a limited volume of distribution, which has been reported to be 11.6 litres (L) in euthyroid volunteers and 14.7 L in primary hypothyroid subjects.19 This is approximately equivalent to the extracellular fluid volume of the body.

Although T4 is subject to multiple metabolic reactions,20–22 the main metabolic route for T4 involves deiodination reactions (removal of iodine) by deiodinase enzymes.23–25 Removal of iodine from the carbon 5 of the outer ring transforms T4 to T3, thus T4 can be regarded somewhat as a pro-hormone for T3. Deiodination of the inner ring of T4 can also occur, leading to the formation of inactive reverse T3(rT3). Approximately half of deiodinised T4 is metabolised to rT3 and half to T3.25,26 Both T3 and rT3 are further metabolised to diiodothyronine (T2), iodothyronamine (T1) and reverse T2 and T1.25,26

The daily turnover rate for T4 is approximately 10 % while it is approximately 50–70 % for T3, with a slightly faster turnover rate in normal volunteers compared with patients with primary hypothyroidism.1,2 This equates to a half-life for T4 of 7.5 days in hypothyroid patients and 6.2 days in euthyroid individuals, while the T3 half-life is approximately 1.4 and 1.0 days for hypothyroid and euthyroid volunteers, respectively.19 Clearance for T4 was similar with 0.056 and 0.054 L/h in hypothyroid and euthyroid subjects, respectively.19 These values are similar to other values reported in hypothyroid patients (0.0385 L/h/70 kg)27 and in normal control subjects (0.053 to 0.064 L/h).28,29

Protein Binding
Both T4 and T3 are highly bound to plasma proteins at greater than 99.8 % (i.e. unbound T4 = 0.02–0.03 %; unbound T3 = 0.2 %) in both euthyroid and primary hypothyroid volunteers.1,19,30,31 Both T4 and T3 bind predominantly (>80 %) to thyroxine-binding globulin (TBG), and to a lesser extent to thyroxine-binding prealbumin and albumin.1,30 Benvenga and Robbins have also demonstrated binding to lipoproteins such as high-density lipoprotein.32,33 The T3 affinity for binding to these proteins is approximately one-thirtieth that of T4,34 which explains the higher turnover rate of T3 compared with T4.

Transporters/Cytochrome Enzymes
Active transport of thyroxine into cells has been recognised for some time.35,36 In vitro studies have shown that organic anion transporting polypeptides (OATP) (such as OATP1A2, OATP1B1, OATP1C1, etc.), monocarboxylate transporter and sodium-taurocholate cotransporting polypeptide are involved at different levels.37–41

However, few articles have been published on the in vivo significance of these transporters on the PK of levothyroxine. Lilja et al. demonstrated the effects of the influx intestinal OATP transporter inhibition by grapefruit juice consumption on levothyroxine absorption.42 They concluded that grapefruit juice had only a minor effect if any on levothyroxine absorption (AUC0-6 dropped by 9 % and Tmax was slightly delayed).42

A transporter that may be induced by levothyroxine is PgP (ABCB1 gene). Jin et al. published results that showed that cyclosporine A trough concentrations were lower in patients taking levothyroxine. In addition, the expression of this transporter was increased and oral cyclosporine A concentrations and bioavailability were lower in rats treated with levothyroxine.43

PK Properties in Special Populations
Table 2 summarises the effects of different conditions on the PK of levothyroxine and additional details are presented below.

Renally Impaired Patients
The kidney plays a significant role in the peripheral metabolism of T4 to T3.1 Therefore, this metabolic route is significantly reduced in renally impaired patients, partially due to accumulated uremic toxins.44,45 In patients with renal disease, there is a reduction in total and free T3 while T4 is less affected;46,47 however, some patients with end-stage renal disease are also diagnosed with hypothyroidism.48 It has also been reported that other metabolic routes may be enhanced, resulting in higher T3 sulphate concentrations.49 The proteinuria associated with the nephrotic syndrome may cause urinary loss of the thyroid hormones bound to the thyroid hormone transport proteins.50,51

The volume of distribution of thyroxine is also increased in patients with renal failure, which is probably due to the decreased protein binding of thyroxine.52 Haemodialysis does not have an impact on levothyroxine requirements in this patient population.47,48 However, kidney transplantation has been shown to affect the levels of thyroid hormones.47 Some authors report that levels of T3 increase with time after transplantation and doses of levothyroxine can consequently be reduced,45,47 while others report the contrary.53 The increased levothyroxine dose could also be due to drug–drug interactions with the medications patients are required to take after kidney transplantation.47

Hepatically Impaired Patients
The liver is a major site for T4 deiodination to T3.1,2 In addition, T3 and T4 are conjugated with glucuronic and sulphuric acids and then excreted in the bile.6 Approximately 20 % of T4 is eliminated in faeces.1 Therefore, it is expected that patients with hepatic impairment would have different levels of circulating T4 and T3 compared with patients with normal hepatic activity. Indeed, several studies have reported similar or higher levels of total and free T4,54,55 decreased levels of total and free T3 and elevated concentrations of rT356–59 in patients with severe cirrhosis compared with normal patients. Other authors have not shown significant reduction in T3 concentrations in patients with different degrees of liver impairment except when patients had severe cirrhosis.60

The clinical impact of severe cirrhosis on thyroid hormone levels is also influenced by other factors, such as lower levels of thyroxine binding proteins such as albumin. Overall, this possibly leads to an increase in free T4 concentrations or the ratio of free T3 to bound T3, meaning that despite overall lower levels of T3, more free T4 and T3 is available. Thus, because levothyroxine is a low-extraction drug, changes in protein binding will affect total levels but not free levels of hormone. Furthermore, increasing the dose of levothyroxine may not compensate for the lack of liver metabolism of T4 to T3.

TSH values are increased in obese patients, which could be attributed to leptin, a hormone produced by adipose tissue that may increase TSH secretion.61,62 Therefore, in such patients, increased levels of TSH do not necessarily indicate hypothyroidism, and TSH should not be the only criteria used to adjust doses.

Some authors have reported higher circulating concentrations of T4 and T3 in obese patients while others have reported lower levels.63,64 Santini et al. reported the lack of a correlation between serum leptin concentrations and the total dose of levothyroxine administered and that adipose tissue had a minor impact on levothyroxine requirements.65 The authors also indicated that lean body mass was superior to actual weight as a predictor of dosage, which is in line with levothyroxine’s small volume of distribution. Greater dose requirements in obese patients are probably attributed to a slightly higher volume of distribution (i.e. higher lean body mass and peripheral mass) compared to non-obese patients rather than to a greater overall weight (fat weight). If weight is used to determine a starting dose in obese patients, total weight may lead to supra-therapeutic doses, therefore using lean body mass might be a better alternative.65

Following conception in euthyroid women, TBG increases quickly with a rise in total T4 concentrations, and decreases in free T4 and TSH in the first trimester.66 T4 production increases 20–40 % in the early part of the first trimester and this continues throughout the pregnancy.67 In hypothyroid women who become pregnant, T4 requirements are also similarly increased, often necessitating an increase in levothyroxine dosage.68 It should be noted that as TSH values are normally lower in the first trimester, increased T4 requirements may not be recognised if TSH is the only marker used to adjust levothyroxine administration doses. Soldin et al. reported that levothyroxine clearance was faster in nonpregnant women at 7.0 L/h versus 4.5 L/h in pregnant women, despite similarities in Tmax and Cmax.67 In addition, PK parameters in pregnant women appeared to be more variable.67

Heskel et al. reported a shorter half-life for T4 in euthyroid children compared with adults (4.95 days for children and almost 7 days in adults).69 They concluded that when considering weight, there was a decreased pool of T4 and an increased elimination rate of thyroxine. Furthermore, Mainwaring et al. reported a shorter half-life for T3 in children undergoing cardiopulmonary bypass compared with adults having the same procedure (seven hours versus close to one day).70 According to the American Thyroid Association71 and the levothyroxine product monograph,72 infants and children require higher doses per weight or per body surface area compared with adults.73 The typical dose can be as high as 10–15 mcg/kg/day for infants from 0–3 months old and it decreases towards adulthood where the typical dose is 1.7 mcg/kg/day.

In healthy elderly individuals, secretion of T4 and T3 and metabolism of T4 to T3 are reduced while rT3 levels appear to increase.74,75 Accordingly, the elimination half-life for T4 is longer and reported to be 9.3 days in patients older than 80 years old.76 Absorption of T4 is also slightly lower for patients above 70.77 Although T4 concentrations do not appear to be decreased in older euthyroid patients, total and free T3 concentrations are reportedly lower in individuals 61–90 years old compared with younger individuals74 , which is expected due to their decreased metabolism. Therefore, measurements of only T4 may be insufficient to explain changes in elderly patients’ thyroid function.

Gastrointestinal Disorders
Certain gastrointestinal disorders, including celiac disease78 and Helicobacter pylori infection17 , can impede the absorption of levothyroxine. As levothyroxine is mainly absorbed through the small intestine, its absorption is compromised in patients with coeliac disease.78 Higher levothyroxine doses were reportedly required in patients with coeliac disease and when patients followed a gluten-free diet, levothyroxine dose requirement was reduced.78,79 H. pylori infection causes chronic gastritis and affects gastric acid secretion in the stomach.17 Levothyroxine doses have been reported to be higher in hypothyroid patients with this disease.17,80 However, following resolution of the infection, Bugdaci et al. recommend that doses be lowered.80 Other gastrointestinal disorders such as inflammatory bowel disease, lactose intolerance and atrophic gastritis have also been demonstrated to affect levothyroxine absorption.

Drug and Food Interactions
Many substances are known to influence T4 or T3 levels and the impact appears to be more significant in hypothyroid patients being treated with exogenous supplementation compared with patients without thyroid pathology, probably due to their intact feedback mechanisms. In addition, interactions with levothyroxine can also occur indirectly via modulation of the HPT axis. All these will be described below and are summarised in Table 3.

The oral absorption of levothyroxine can be impaired by various substances, such as food13,81–83 , soy bean,84–91 papaya92 and grapefruit.42 Benvenga and colleagues have demonstrated that coffee can also impair the absorption of certain levothyroxine formulations.93,94

Drugs Drugs
can alter the PKs of thyroid hormones in various ways.95 Drugs that decrease TSH secretion (dopamine,96–100 glucocorticoids,101,102 octreotide103,104 and rexinoids105,106 ) lead to decreased thyroid hormone concentrations, while thyroid hormone synthesis is interfered with by other drugs,107 such as lithium, iodine108 , tolbutamide, sulphonamides and amiodarone.109,110

Proton-pump inhibitors, such as omeprazole17 and lansoprazole,18 have also been shown to influence the absorption of levothyroxine, as assessed by TSH levels in patients, since normal gastric acid secretion plays a major role in the absorption of thyroxine. Interestingly, others found that in healthy volunteers, famotidine and esomeprazole had no such effect.111 Aluminium hydroxide112–114 , dietary fibre115 , calcium carbonate,116–119 calcium citrate,120 calcium acetate, ferrous sulphate,121–123 cholestyramine124 and colsevelam125,126 decrease levothyroxine absorption by binding to it and forming complexes that are not absorbed. Sucralphate127 may decrease levothyroxine absorption by interfering with its intra-luminal transport or by binding to it.82 .Other products such as phosphate binders,126,128,129 orlistat130 and cimetidine131 also appear to decrease the absorption of levothyroxine, although the interaction mechanism/s is/are not as clearly defined.

Drug interactions can also influence other PK processes. For instance, the administration of beta blockers such as acebutolol, oxprenolol and timolol appear to modify the extracellular distribution of T3, thereby decreasing T3 levels.132 Changes in protein binding can also influence the PK of levothyroxine, as decreased protein binding is associated with greater levels of free levothyroxine, which is then more readily eliminated from the systemic circulation. Drugs that decrease levothyroxine protein binding include carbamazepine,133 androgens, anabolic steroids,134,135 and nicotinic acid.136,137 Certain drugs are associated with transient increases in free T4 levels due to inhibition of protein binding,107 including high-dose furosemide,138 salicylates139–141 and heparin.140,142 Conversely, drugs that increase protein binding are associated with a reduced clearance of levothyroxine. Such drugs include ethinyl oestradiol,143–145 tamoxifen,146 heroin, methadone,147–150 mitotane and fluorouracil.151,152

Finally, some drug interactions with levothyroxine can be explained by an effect on its metabolism, such as the extrathyroidal conversion rate of T4 to T3. Certain drugs, such as propranolol28,29,153,154 and amiodarone,107 reduce this metabolism. Conversely, carbamazepine,133,155–158 phenobarbital,159,160 rifampin107 and phenytoin155,161 induce liver microsomal enzymes and increase this peripheral metabolism.

Available Formulations
Commercial levothyroxine oral formulations available in North America and Europe include powders for intravenous solutions, tablets (e.g. Synthroid®, Levo-T™, Levothroid®, Levoxyl®, Unithroid®, Eltroxin®, Elthyrone®, Euthyrox®, Eferox®, Berlthyrox®, Letrox®, Tirosint®), soft gel capsules (Tirosint®) and oral solutions (Eltroxin®, Tirosint®oral drops and Tirosint®oral solution in unit-dose ampules).

There are advantages and disadvantages that are unique to the formulation type and not to levothyroxine per se. For instance, while tablets and capsules offer the advantage of precise dosing, solutions and liquids can be easier to swallow for children or the elderly. Formulation differences that are specific to levothyroxine also exist. The influence of pH on dissolution profiles of tablets and soft gel capsules is dissimilar,162 as well as the negative impact of coffee intake on levothyroxine absorption.93,94

The existence of multiple levothyroxine formulations is also the result of the availability of many generic versions of these compounds. Many studies have been published describing comparisons of the PK properties of various levothyroxine formulations163–181 and various approaches have been employed since bioequivalence assessments of levothyroxine are complicated by baseline levels, feedback mechanisms and by the fact that levothyroxine is considered by some to be a ‘narrow therapeutic index’ (NTI) drug, which some believe merit more stringent criteria (confidence intervals of 90–111 % rather than the standard 80–125 %, or stability throughout the shelf-life of +/-5 % instead of +/-10 %). For this reason, specific guidelines pertaining to assessing the bioequivalence of levothyroxine formulations have been published, in particular by the US Food and Drug Administration (FDA).

Current regulatory guidelines published by the FDA recommend that bioequivalence of levothyroxine formulations be assessed by comparing PK measures of T4.182 The underlying assumption regarding the use of T4 rather than TSH or T3 is that systemic T4 levels reflect the levels at the site of action, and that a relationship exists between the efficacy and safety of the product and its systemic levels. Despite TSH sensitivity to changes in thyroid hormone level, TSH is not used to assess bioequivalence of thyroid formulations because it is a secondary response to levothyroxine and there is a significant time delay between the administration of exogenous levothyroxine and the changes noted in TSH levels. In addition, it is simply not a direct measure of levothyroxine- administered product, as are baseline-adjusted T4 concentrations.

Because levothyroxine is an endogenous compound, it is important to take baseline levels into consideration when performing bioequivalence assessments to avoid biasing comparisons which can lead to failure in distinguishing true differences between formulations.183 Current FDA bioequivalence guidelines require that supra-therapeutic doses of levothyroxine (600 mcg) be administered and that levothyroxine PK parameters be corrected for individual baseline values. This minimises the effect of endogenous concentrations on bioequivalence assessments182,184 by ensuring a high signal (concentrations related to exogenous levothyroxine) to noise (endogenous levels) ratio.

In addition to some of the recommendations described above, the FDA also stipulates that a levothyroxine product must have a 95–105 % potency specification over its entire shelf-life instead of previously accepted potency limits of 90–110 %.185 This was established to ensure greater consistency in levothyroxine administered to patients and to reduce possibly large fluctuations in drug concentrations.

Thus, recommendations from current regulatory guidelines regarding study design and baseline adjustment of PK parameters ensure that a conservative approach to bioequivalence of levothyroxine formulations is adopted.

Although levothyroxine has long been a mainstay in the treatment of hypothyroidism, its optimal use often remains elusive. Not only are thyroid hormones levels governed by sensitive and complicated feedback mechanisms, but they are also subject to the influence of disease, the intake of food and the use of concomitant medication. While these competing factors can pose a challenge for clinicians, a thorough comprehension of these elements as well as other PK considerations will ultimately be beneficial for the patient.

Article Information:

Philippe Colucci, Corinne Seng Yue and Murray Ducharme are employees of Learn and Confirm Inc. and received funding from Institut Biochimique SA (IBSA). Salvatore Benvenga received from IBSA new L-thyroxine formulations for the conduct of clinical studies.


Salvatore Benvenga, Interdepartmental Program of Molecular & Clinical Endocrinology and Women’s Endocrine Health, Policlinico Universitario di Messina padiglione H, 4 piano 98125 Messina, Italy. E:;




  1. Haynes R, Thyroid and Antithyroid Drugs. In: Gilman AG, Rall TW, Nies AS, Taylor P (editors). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, New York: McGrawHill, Inc., 1993;1361–83.
  2. Dong BJ, Thyroid and Parathyroid Disorders. In: Herfindal ET, Gourley DR, Hart LL (editors). Clinical Pharmacy and Therapeutics, Baltimore: Williams & Wilkins, 1992;267–306.
  3. Pangaro LN, Physiology of the Thyroid Gland. In: Becker KL (editor). Principles and Practice of Endocrinology and Metabolism, Philadelphia: J.B. Lippincott Company, 1990.
  4. Mandel SJ, Brent GA, Larsen PR, Levothyroxine therapy in patients with thyroid disease, Ann Intern Med, 1993;119(6):492–502.
  5. Cavalieri RR, Rapoport B, Impaired Peripheral Conversion of Thyroxine to Triiodothyronine, Annu Rev Med, 1977;28:57–65.
  6. LoPresti JS, Eigen A, Kaptein E, et al., Alterations in 3,3’5’-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man, J Clin Invest, 1989;84(5):1650–56.
  7. Sarfaraz NK, In: Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Product, Boca Raton: CRC Press LLC, 2004;151–2.
  8. Almandoz J, Gharib H, Hypothyroidism: Etiology, Diagnosis and Management, Med Clin N Am, 2012;96(2):203–21.
  9. Garber J, Cobin R, Gharib H, et al., Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association, Thyroid, 2012;22(12):1200–35.
  10. Hays MT, Thyroid hormone and the gut, Endocr Res, 1988;14(2–3):203–24.
  11. Hays MT, Localization of human thyroxine absorption, Thyroid, 1991;1(3):241–8.
  12. Stone E, Leiter LA, Lambert JR, et al., L-thyroxine absorption in patients with short bowel, J Clin Endocrinol Metab, 1984;59(1):139–41.
  13. Benvenga S, Bartolone L, Squadrito S, et al., Delayed intestinal absorption of levothyroxine, Thyroid, 1995;5(4):249–53.
  14. Wenzel KW, Kirschsieper HE, Aspects of the absorption of oral L-thyroxine in normal man, Metabolism, 1977;26(1):1–8.
  15. Read DG, Hays MT, Hershman JM, Absorption of oral thyroxine in hypothyroid and normal man, J Clin Endocrinol Metab, 1970;30(6):798–9.
  16. Hasselström K, Siersbaek-Nielsen K, Lumholtz IB, et al., The bioavailability of thyroxine and 3,5,3’-triiodothyronine in normal subjects and in hyper- and hypothyroid patients, Acta Endocrinol (Copenh), 1985;110(4):486–6.
  17. Centanni M, Gargano L, Canettieri G, et al., Thyroxine in goiter, Helicobacter pyloriinfection, and chronic gastritis, N Engl J Med, 2006;354(17):1787–95.
  18. Sachmechi I, Reich D, Aninyei M, et al., Effect of proton pump inhibitors on serum thyroid-stimulating hormone level in euthyroid patients treated with levothyroxine for hypothyroidism, Endocr Pract, 2007;13(4):345–9.
  19. Nicoloff JT, Low JC, Dussault JH, Fisher DA, Simultaneous Measurement of Thyroxine and Triiodothyronine Peripheral Turnover Kinetics in Man, J Clin Invest, 1972;51(3):473–83.
  20. Mol JA, Visser TJ. Rapid and selective inner ring deiodination of thyroxine sulfate by rat liver deiodinase, Endocrinology, 1985;117(1):8–12.
  21. Pittman CS, Shimizu T, Burger A, Chambers Jr JB, The nondeiodinative pathways of thyroxine metabolism: 3,5,3’,5-tetraiodothyroacetic acid turnover in normal and fasting human subjects, J Clin Endocrinol Metab, 1980;50(4):712–16.
  22. Balsam A, Sexton F, Borges M, Ingbar SH, Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism, J Clin Invest, 1983;72(4):1234–45.
  23. Braverman LE, Ingbar SH, Sterling K, Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects, J Clin Invest, 1970;49(5):855–64.
  24. Pittman CS, Chambers JB, Read VH, The extrathyroidal conversion rate of thyroxine to triiodothyronine in normal man, J Clin Invest, 1971;50(6):1187–96.
  25. Robbins J, Factors altering thyroid hormone metabolism, Environ Health Perspect, 1981;38:65–70.
  26. Engler D, Merkelbach U, Steiger G, Burger AG, The monodeiodination of triiodothyronine and reverse triiodothyronine in man: a quantitative evaluation of the pathway by the use of turnover rate techniques, J Clin Endocrinol Metab, 1984;58(1):49–61.
  27. Fish LH, Schwartz HL, Cavanaugh J, et al., Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans, N Engl J Med, 1987;316(13):764–70.
  28. Chambers Jr J, Pittman C, Suda A, The effects of propranolol on thyroxine metabolism and triiodothyronines production in man, J Clin Pharmacol, 1982;22(2–3):110–16.
  29. van der Heijden J, Krenning E, van Toor H, et al., Threecompartmental analysis of effects of D-propranolol on thyroid hormone kinetics, Am J Physiol Endocrinol Metab, 1988;255:E80–E86.
  30. Utiger RD, Serum triiodothyronine in man, Annu Rev Med, 1974;25:289–302.
  31. Braverman LE, Vagenakis A, Downs P, et al., Effects of replacement doses of sodium L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man, J Clin Invest, 1973;52(5):1010–7.
  32. Benvenga S, Robbins J, Lipoprotein-thyroid hormone interactions, Trends Endocrinol Metab, 1993;4(6):194–8.
  33. Benvenga S, Robbins J, Altered thyroid hormone binding to plasma lipoproteins in hypothyroidism, Thyroid, 1996;6(6):595–600.
  34. Hao YL, Tabachnick M, Thyroxine-protein interactions. VII. Effect of thyroxine analogs on the binding of 125-I-thyroxine to highly purified human thyroxine-binding globulin, Endocrinology, 1971;88(1):81–92.
  35. Stitzer LK, Jacquez JA, Neutral amino acid transport pathways in uptake of L-thyroxine by Ehrlich ascites cells, Am J Physiol, 1975;229(1):172–7.
  36. Rao GS, Eckel J, Rao ML, Breuer H, Uptake of thyroid hormone by isolated rat liver cells, Biochem Biophys Res Commun, 1976;73(1):98–104.
  37. Friesema EC, Docter R, Moerings EP, et al., Identification of thyroid hormone transporters, Biochem Biophys Res Commun, 1999;254(2):497–501.
  38. Fujiwara K, Adachi H, Nishio T, et al., Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner, Endocrinology, 2001;142(5):2005–12.
  39. Friesema EC, Jansen J, Milic C, Visser TJ, Thyroid hormone transporters, Vitam Horm, 2005;70:137–67.
  40. Visser WE, Friesema EC, Jansen J, Visser TJ, Thyroid hormone transport by monocarboxylate transporters, Best Pract Res Clin Endocrinol Metab, 2007;21(2):223–36.
  41. Hagenbuch B, Cellular entry of thyroid hormones by organic anion transporting polypeptides, Best Pract Res Clin Endocrinol Metab, 2007;21(2):209–21.
  42. Lilja J, Laitinen K, Neuvonen P, Effects of grapefruit juice on the absorption of levothyroxine, Br J Clin Pharmacol, 2004;60(3):337–41.
  43. Jin M, Shimada T, Shintani M, et al., Long-term levothyroxine treatment decreases the oral bioavailability of cyclosporin A by inducing P-glycoprotein in small intestine, Drug Metab Pharmacokinet, 2005;20(5):324–30.
  44. Engler D, Burger AG, The deiodination of the iodothyronines and of their derivatives in man, Endocr Rev, 1984;5(2):151–84.
  45. Thomas MC, Mathew TH, Russ GR, Changes in thyroxine requirements in patients with hypothyroidism undergoing renal transplantation, Am J Kidney Dis, 2002;39(2):354–7.
  46. Giordano C, De Santo NG, Carella C, et al., Thyroid status and nephron loss – a study in patients with chronic renal failure, end stage renal disease and/or on hemodialysis, Int J Artif Organs, 1984;7(3):119–22.
  47. Reinhardt W, Misch C, Jockenhövel F, et al., Triiodothyronine (T3) reflects renal graft function after renal transplantation, Clin Endocrinol (Oxf), 1997;46(5):563–9.
  48. Yonemura K, Nakajima T, Suzuki T, et al., Low free thyroxine concentrations and deficient nocturnal surge of thyroid-stimulating hormone in haemodialysed patients compared with undialysed patients, Nephrol Dial Transplant, 2000;15(5):668–72.
  49. Santini F, Chiovato L, Bartalena L, et al., Study of serum 3,5,3’-triiodothyronine sulfate concentration in patients with systemic non-thyroidal illness, Eur J Endocrinol, 1996;134(1):45–9.
  50. De Luca F, Gemelli M, Pandullo E, et al., Changes in thyroid function tests in infantile nephrotic syndrome, Horm Metab Res, 1983;15(5):258–9.
  51. Trimarchi F, Gemelli M, Benvenga S, et al., Transient congenital hypothyroidism in an infant with congenital nephrosis of Finnish type, Acta Paediatr Scand, 1983;72(1): 145–7.
  52. Kaptein EM, Kaptein JS, Chang EI, et al., Thyroxine transfer and distribution in critical nonthyroidal illnesses, chronic renal failure, and chronic ethanol abuse, J Clin Endocrinol Metab, 1987;65(4):606–16.
  53. Lim VS, Fang VS, Katz AI, Refetoff S, Thyroid dysfunction in chronic renal failure. A study of the pituitary-thyroid axis and peripheral turnover kinetics of thyroxine and triiodothyronine, J Clin Invest, 1977;60(3):522–34.
  54. Nomura S, Pittman CS, Chambers Jr JB, et al., Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis, J Clin Invest, 1975;56(3):643–52.
  55. Green JR, Thyroid function in chronic liver disease, Z Gastroenterol, 1979;17(7):447–51.
  56. Chopra IJ, Solomon DH, Chopra U, et al., Alterations in circulating thyroid hormones and thyrotropin in hepatic cirrhosis: evidence for euthyroidism despite subnormal serum triiodothyronine, J Clin Endocrinol Metab, 1974;39(3): 501–11.
  57. Faber J, Thomsen HF, Lumholtz IB, et al., Kinetic studies of thyroxine, 3,5,3’-triiodothyronine, 3,3,5’-triiodothyronine, 3’,5’-diiodothyronine, 3,3’-diiodothyronine, and 3’-monoiodothyronine in patients with liver cirrhosis, J Clin Endocrinol Metab, 1981;53(5):978–84.
  58. Kabadi UM, Premachandra BN, Serum T3 and reverse T3 levels in hepatic cirrhosis: relation to hepatocellular damage and normalization on improvement in liver dysfunction, Am J Gastroenterol, 1983;78(11):750–55.
  59. Hepner GW, Chopra IJ, Serum thyroid hormone levels in patients with liver disease, Arch Intern Med, 1979;139(10):1117–20.
  60. Yamanaka T, Ido K, Kimura K, Saito T, Serum levels of thyroid hormones in liver diseases, Clin Chim Acta, 1980;101(1): 45–55.
  61. Pinkney JH, Goodrick SJ, Katz J, et al., Leptin and the pituitary-thyroid axis: a comparative study in lean, obese, hypothyroid and hyperthyroid subjects, Clin Endocrinol (Oxf), 1998;49(5):583–8.
  62. Casanueva FF, Dieguez C, Neuroendocrine regulation and actions of leptin, Front Neuroendocrinol (Lausanne), 1999;20(4):317–63.
  63. Michalaki MA, Gkotsina MI, Mamali I, et al., Impaired pharmacokinetics of levothyroxine in severely obese volunteers, Thyroid, 2011;21(5):477-81.
  64. Marzullo P, Minocci A, Tagliaferri MA, et al., Investigations of thyroid hormones and antibodies in obesity: leptin levels are associated with thyroid autoimmunity independent of bioanthropometric, hormonal, and weight-related determinants, J Clin Endocrinol Metab, 2010;95(8):3965–72.
  65. Santini F, Pinchera A, Marsili A, et al., Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases, J Clin Endocrinol Metab, 2005;90(1):124–7.
  66. Glinoer D, The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology, Endocr Rev, 1997;18(3):404–33.
  67. Soldin OP, Soldin SJ, Vinks AA, et al., Longitudinal comparison of thyroxine pharmacokinetics between pregnant and nonpregnant women: a stable isotope study, Ther Drug Monit, 2010;32(6):767–73.
  68. Mandel SJ, Larsen PR, Seely EW, Brent GA, Increased need for thyroxine during pregnancy in women with primary hypothyroidism, N Engl J Med, 1990;323(2):91–6.
  69. Haddad HM, Rates of I 131-labeled thyroxine metabolism in euthyroid children, J Clin Invest, 1960;39(10):1590–94.
  70. Mainwaring RD, Capparelli E, Schell K, et al., Pharmacokinetic evaluation of triiodothyronine supplementation in children after modified Fontan procedure, Circulation, 2000;101(12):1423–9.
  71. Susan RR, Rosalind SB, Update of newborn screening and therapy for congenital hypothyroidism, Pediatrics, 2006; 117(6):2290–2303.
  72. Abbott Laboratories Ltd (Synthroid). Health Canada Product Information, 2010, accessed 1 January 2013 (available at: do?code=19589&lang=eng).
  73. Mercury Pharma Group Ltd (Eltroxin). electronic Medicines Compendium (eMC), October 2012, 7 January 2013.
  74. Davis JD, Stern RA, Flashman LA, Cognitive and neuropsychiatric aspects of subclinical hypothyroidism: significance in the elderly, Curr Psychiatry Rep, 2003;5(5): 384–90.
  75. Bégin ME, Langlois MF, Lorrain D, Cunnane SC, Thyroid Function and Cognition during Aging, Curr Gerontol Geriatr Res, 2008:474868.
  76. Drinka PJ, Abnormal TSH: a rational approach to the older patient, Geriatrics, 1999;54(8):63–5.
  77. Hays MT, Nielsen KR, Human thyroxine absorption: age effects and methodological analyses, Thyroid, 1994;4(1): 55–64.
  78. Collins D, Wilcox R, Nathan M, Zubarik R, Celiac disease and hypothyroidism, Am J Med, 2012;125(3):278–82.
  79. Virili C, Bassotti G, Santaguida MG, et al. Atypical celiac disease as cause of increased need for thyroxine: a systematic study, J Clin Endocrinol Metab, 2012;97(3): E419–22.
  80. Bugdaci MS, Zuhur SS, Sokmen M, et al., The role of Helicobacter pyloriin patients with hypothyroidism in whom could not be achieved normal thyrotropin levels despite treatment with high doses of thyroxine, Helicobacter, 2011; 16(2):124–30.
  81. American Society of Health-System Pharmacists, Inc., AHFS Drug Information, Bethesda, MD, 2011.
  82. Liwanpo L, Hershman J, Conditions and drugs interfering with thyroxine absorption, Best Pract Res Clin Endocrinol Metab, 2009;23(6):781–92
  83. Woeber K, Treatment of Hypothyroidism. In: Braverman LE, Uttiger RD (editors), The Thyroid: A Fundamental & Clinical Textbook. 9th ed, Philadelphia: Lippincott Williams & Wilkins, 2005.
  84. Fruzza A, Demeterco-Berggren C, Jones K, Unawareness of the Effects of Soy Intake on the Management of Congenital Hypothyroidism, Pediatrics, 2012;130(3):e699–702.
  85. Van Wyk J, Arnold M, Wynn J, Pepper F, The Effects of a Soybean Product on Thyroid Function in Humans, Pediatrics, 1959;24(5):752–60.
  86. Hydovitz J, Occurrence of goiter in an infant on a soy diet, N Engl J Med, 1960;262(7):351–3.
  87. Chorazy P, Himelhoch S, Hopwood N, et al., Persistent Hypothyroidism in an Infant Receiving a Soy Formula: Case Report and Review of the Literature, Pediatrics, 1995;96(1):148–50.
  88. Pinchera A, MacGillivray M, Crawford J, Freeman A, Thyroid refractoriness in an athyreotic cretin fed soybean formula, N Engl J Med, 1965;273(2):83–7.
  89. Jabbar M, Larrea J, Shaw R, Abnormal thyroid function tests in infants with congenital hypothyroidism: the influence of soy-based formula, J Am Coll Nutr, 1997;16(3):280–82.
  90. Conrad S, Chiu H, Silverman B, Soy formula complicates management of congenital hypothyroidism, Arch Dis Child, 2004;89(1):37–40.
  91. Marini H, Polito F, Adamo E, et al., Update on genistein and thyroid: an overall message of safety, Front Endocrinol (Lausanne), 2012;3:1–4.
  92. Deiana L, Marini S, Mariotti S, Ingestion of large amounts of papaya fruit and impaired effectiveness of levothyroxine therapy, Endocr Pract, 2012;18(1):98–100.
  93. Benvenga S, Bartolone L, Pappalardo M, et al., Altered intestinal absorption of L-thyroxine caused by coffee, Thyroid, 2008;18(3):293–301.
  94. Vita R, Saraceno G, Trimarchi F, Benvenga S, A novel formulation of L-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations, Endocrine, 2013;43(1):154–60.
  95. Benvenga S, Ruggeri RM, Trumarchi F, Thyroid and drugs. In: Monaco F (editor), Thyroid diseases, Boca Raton: CRC Press, 2012;469–92.
  96. Cooper DS, Klibanski A, Ridgway EC, Dopaminergic Modulation of TSH and its Subunits: In Vivo and In Vitro Studies, Clin Endocrinol (Oxf), 1983;18(3):265-275.
  97. Agner T, Hagen C, Andersen AN, Djursing H, Increased Dopaminergic Activity Inhibits Basal and MetoclopramideStimulated Prolactin and Thyrotropin Secretion, J Clin Endocrinol Metab, 1986;62(4):778–82.
  98. Boesgaard S, Hagen C, Hangaard J, et al., Effect of Dopamine and a Dopamine D-1 Receptor Agonist on Pulsatile Thyrotrophin Secretion in Normal Women, Clin Endocrinol (Oxf), 1990;32(4):423–31.
  99. Kerr D, Singh V, McConway M, et al., Circadian variation of thyrotrophin, determined by ultrasensitive immunoradiometric assay, and the effect of low dose nocturnal dopamine infusion, Clin Sci, 1987;72(6):737–41.
  100. Brabant G, Prank K, Hoang-Vu C, et al., Hypothalamic Regulation of Pulsatile Thyrotropin Secretion, J Clin Endocrinol Metab, 1991;72(1):145–50.
  101. Brabant A, Brabant G, Schuemeyer T, et al., The role of glucocorticoids in the regulation of thyrotropin, Acta Endocrinol, 1989;121(1):95–100.
  102. Samuels M, Luther M, Henry P, Ridgway E, Effects of hydrocortisone on pulsatile pituitary glycoprotein secretion, J Clin Endocrinol Metab, 1994;78(1):211–15.
  103. Bertherat J, Brue T, Enjalbert A, Gunz G, et al., Somatostatin receptors on thyrotropin-secreting pituitary adenomas: comparison with the inhibitory effects of octreotide upon in vivo and in vitro hormonal secretions, J Clin Endocrinol Metab,1992;75(2):540–46.
  104. Christensen S, Weeke J, Orskov H, et al., Long-term efficacy and tolerability of octreotide treatment in acromegaly, Metabolism, 1992;41(9):44–50.
  105. Sherman S, Gopal J, Haugen B, et al., Central hypothyroidism associated with retinoid X receptor-selective ligands, N Engl J Med, 1999;340(14):1075–9.
  106. Golden W, Weber K, Hernandez T, et al., Single-dose rexinoid rapidly and specifically suppresses serum thyrotropin in normal subjects, J Clin Endocrinol Metab, 2007;92(1):124–30.
  107. Surks M, Sievert R, Drugs and Thyroid Function, N Engl J Med, 1995;333(25):1688–94.
  108. Braverman L, Effects of iodine on thyroid function in man, Trans Am Clin Climatol Assoc, 1991;102:143–51.
  109. Figge H, Figge J, The effects of amiodarone on thyroid hormone function: a review of the physiology and clinical manifestations, J Clin Pharmacol, 1990;30(7):588–95.
  110. Burger A, Dinichert D, Nicod P, et al., Effect of Amiodarone on Serum Triiodothyronine, Reverse Triiodothyronine, Thyroxin, and Thyrotropin, J Clin Invest, 1976;58(2):255–9.
  111. Ananthakrishnan S, Braverman L, Levin R, et al., The effect of famotidine, esomeprazole, and ezetimibe on levothyroxine absorption, Thyroid, 2008;18(5):493–8.
  112. Sperber A, Liel Y, Evidence for Interference With the Intestinal Absorption of Levothyroxine Sodium by Aluminum Hydroxide, Arch Intern Med, 1992;152(1):183–4.
  113. Liel Y, Sperber A, Shany S, Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide, Am J Med, 1994; 97(4):363–5.
  114. Mersebach H, Rasmussen A, Kirkegaard L, Feldt-Rasmussen U, Intestinal adsorption of levothyroxine by antacids and laxatives: case stories and in vitro experiments, Pharmacol Toxicol, 1999;84(3):107–9.
  115. Liel Y, Harman-Boehm I, Shany S, Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients, J Clin Endocrinol Metab, 1996;81(2):857–9.
  116. Singh N, Singh P, Hershman J, Effect of calcium carbonate on the absorption of levothyroxine, JAMA, 2000;283(21):2822–5.
  117. Csako G, McGriff N, Rotman-Pikielny P, et al., Exaggerated levothyroxine malabsorption due to calcium carbonate supplementation in gastrointestinal disorders, Ann Pharmacother, 2001;35(12):1578–83.
  118. Mazokopakis E, Giannakopoulos T, Starakis I, Interaction between levothyroxine and calcium carbonate, Can Fam Physician, 2008;54(1):39.
  119. Singh N, Weisler S, Hershman J, The acute effect of calcium carbonate on the intestinal absorption of levothyroxine, Thyroid, 2001;11(10):967–71.
  120. Zamfirescu I, Carlson H, Absorption of Levothyroxine When Coadministered with Various Calcium Formulations, Thyroid, 2011;21(5):483–6.
  121. Campbell N, Hasinoff B, Stalts H, et al., Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism, Ann Intern Med, 1992;117(12):1010–13.
  122. Fiaux E, Kadri K, Levasseur C, et al., Hypothyroidism as the result of drug interaction between ferrous sulfate and levothyroxine, Rev Med Interne, 2010;31(10):e4–5.
  123. Shakir K, Chute J, Aprill B, Lazarus A, Ferrous Sulfate-Induced Increase in Requirement for Thyroxine in a Patient With Primary Hypothyroidism, South Med J, 1997;90(6):637–9.
  124. Northcutt R, Stiel J, Hollifield J, Stant EJ, The influence of cholestyramine on thyroxine absorption, JAMA, 1969; 208(10):1857–61.
  125. Brown K, Armstrong I, Wang A, et al., Effect of the Bile Acid Sequestran Colesevelam on the Pharmacokinetics of Pioglitazone, Repaglinide, Estrogen Estradiol, Norethindrone, Levothyroxine, and Glyburide, J Clin Pharmacol, 2010;50(5): 554–65.
  126. Weitzman S, Ginsburg K, Carlson H, Colesevelam Hydrochloride and Lanthanum Carbonate Interfere with the Absorption of Levothyroxine, Thyroid, 2009;19(1):77–9.
  127. Sherman S, Tielens E, Ladenson P, Sucralfate causes malabsorption of L-thyroxine, Am J Med, 1994;96(6):531–5.
  128. Arnadottir M, Johannesson A, Phosphate binders and timing of levothyroxine administration, Nephrol Dial Transplant, 2008;23(1):420.
  129. Diskin C, Stokes T, Dansby L, et al., Effect of phosphate binders upon TSH and L-thyroxine dose in patients on thyroid replacement, Int Urol Nephrol, 2007;39(2):599–602.
  130. Madhava K, Hartley A, Hypothyroidism in thyroid carcinoma follow-up: orlistat may inhibit the absorption of thyroxine, Clin Oncol, 2005;17(6):492.
  131. Jonderko G, Jonderko K, Marcisz C, Kotulska A, Effect of cimetidine and ranitidine on absorption of [125I] levothyroxine administered orally, Acta Pharmacologica Sinica, 1992;13(5):391–4.
  132. Kayser L, Perrild H, Petersen P, Skovsted L, Hansen J. et al., Acute beta-blockade changes the extracellular distribution of thyroid hormones, J Endocrinol Invest, 1990;13(4):277–81.
  133. Simko J, Horacek J, Carbamazepine and risk of hypothyroidism: a prospective study, Acta Neurol Scand, 2007;116(5):317–21.
  134. Deyssig R, Weissel M, Ingestion of androgenic-anabolic steroids induces mild thyroidal impairment in male body builders, J Clin Endocrinol Metab, 1993;76(4):1069–71.
  135. Malarkey W, Strauss R, Leizman D, et al., Endocrine effects in female weight lifters who self-administer testosterone and anabolic steroids, Am J Obstet Gynecol, 1991;165(5):1385–90.
  136. Cashin-Hemphill L, Spencer C, Nicoloff J, et al., Alterations in serum thyroid hormonal indices with colestipol-niacin therapy, Ann Intern Med, 1987;107(3):324–9.
  137. Shakir K, Kroll S, Aprill B, et al., Nicotinic acid decreases serum thyroid hormone levels while maintaining a euthyroid state, Mayo Clin Proc, 1995;70(6):556–8.
  138. Stockigt J, Lim C, Barlow J, et al., Interaction of furosemide with serum thyroxine-binding sites: in vivo and in vitro studies and comparison with other inhibitors, J Clin Endocrinol Metab, 1985;60(5):1025–31.
  139. Larsen P, Salicylate-Induced Increases in Free Triiodothyronine in Human Serum, J Clin Invest, 1972;51(5):1125–34.
  140. Faber J, Waetjen I, Siersbaek-Nielsen K, Free thyroxine measured in undiluted serum by dialysis and ultrafiltration: Effects of non-thyroidal illness, and an acute load of salicylate or heparin, Clinica Chimica Acta, 1993;223(1–2): 150–67.
  141. McConnell R, Abnormal Thyroid Function Test Results in Patients Taking Salsalate, JAMA, 1992;267(9):1242–3.
  142. Hershman J, Jones C, Bailey A, Reciprocal Changes in Serum Thyrotropin and Free Thyroxine Produced by Heparin, J Clin Endocrinol Metab, 1972;34(3):574–9
  143. Steingold K, Matt D, DeZiegler D, et al., Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure, J Clin Endocrinol Metab, 1991;73(2):275–80.
  144. Kuhl H, Jung-Hoffman C, Weber J, Boehm B. The effect of a biphasic desogestrel-containing oral contraceptive on carbohydrate metabolism various hormonal parameters, Contraception, 1993;47(1):55–68.
  145. Sanger N, Stahlberg S, Manthey T, et al., Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters: conventional vs. extended-cycle use, Contraception, 2008;77(6):420–25.
  146. Mamby C, Love R, Lee K, Thyroid function test changes with adjuvant tamoxifen therapy in postmenopausal women with breast cancer, J Clin Oncol, 1995;13(4):854–7.
  147. Azizi F, Vagenakis A, Portnay G, et al., Thyroxine transport and metabolism in methadone and heroin addicts, Ann Intern Med, 1974;80(2):194–9.
  148. English T, Ruxton D, Eastman C, Abnormalities in thyroid function associated with chronic therapy with methadone, Clin Chem, 1988;34(11):2202–4.
  149. Novick D, Poretsky L, Kalin M, Methadone and thyroid function tests, Clin Chem, 1989;35(8):1807–8.
  150. Schussler G, Stimmel B, Korn F, Increased serum thyroid hormone binding in narcotic addicts is due to liver disease, Am J Drug Alcohol Abuse, 1980;7(3–4):379–87.
  151. van Seters A, Moolenaar A, Mitotane increases the blood levels of hormone-binding proteins, Acta Endocrinol, 1991;124(5):526–33.
  152. Beex L, Ross A, Smals A, Kloppenborg P, 5-fluorouracilinduced increase of total serum thyroxine and triiodothyronine, Cancer Treat Rep, 1977;61(7):1291–5.
  153. Lumholtz I, Siersbaek-Nielsen K, Faber J, et al., Effect of propranolol on extrathyroidal metabolism of thyroxine and 3,3’,5-triiodothyronine evaluated by noncompartmental kinetics, J Clin Endocrinol Metab, 1978;47(3):587–9.
  154. Wiersinga W, Propranolol and thyroid hormone metabolism, Thyroid, 1991;1(3):273–7.
  155. Liewendsahl K, Tikanoja S, Helenius T, Majuri H, Free Thyroxin and Free Triiodothyronine as Measured by Equilibrium Dialysis and Analog Radioimmunoassay in Serum of Patients Taking Phenytoin and Carbamazepine, Clin Chem, 1985; 31(12):1993–6.
  156. Bentsen K, Gram L, Veje A, Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate, Acta Neurol Scand, 1983;67(4):235–41.
  157. Isojarvi J, Pakarinen A, Myllyla V, Thyroid Function in Epileptic Patients Treated With Carbamazepine, Arch Neurol, 1989; 46(11):1175–8.
  158. De Luca F, Arrigo T, Pandullo E, et al., Changes in thyroid function tests induced by 2 month carbamazepine treatment in L-thyroxine-substituted hypothyroid children, Eur J Pediatr, 1986;145(1–2):77–9.
  159. Oppenheimer J, Bernstein G, Surks M, Increased Thyroxine Turnover and Thyroidal Function after Stimulation of Hepatocellular Binding of Thyroxine by Phenobarbital, J Clin Invest, 1968;47(6):1399–1406.
  160. Cavalieri R, Sung L, Becker C, Effects of Phenobarbital on Thyroxine and Triiodothyronine Kinetics in Graves’ Disease, J Clin Endocrinol Metab, 1973;37(2):308–16.
  161. Smith P, Surks M, Multiple Effects of 5,5’-Diphenylhydantoin on the Thyroid Hormone System, Endocr Rev, 1984;5(4):514.
  162. Pabla D, Akhlaghi F, Zia H, A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry, Eur J Pharm Biopharm, 2009;72(1):105–10.
  163. Yamamoto T, Tablet formulation of levothyroxine is absorbed less well than powdered levothyroxine, Thyroid, 2003;13(12): 1177–81.
  164. Olveira G, Almaraz M, Soriguer F, et al., Altered bioavailability due to changes in the formulation of a commercial preparation of levothyroxine in patients with differentiatd thyroid carcinoma, Clin Endocrinol (Oxf), 1997;46(6):707–11.
  165. Escalante D, Arem N, Arem R, Assessment of Interchangeability of Two Brands of Levothyroxine Preparations With a Third-Generation TSH Assay, Am J Med, 1995;98(4):374–8.
  166. Colucci P, D’Angelo P, Mautone G, et al., Pharmacokinetic Equivalence of a Levothyroxine Sodium Soft Capsule Manufactured Using the New Food and Drug Administration Potency Guidelines in Healthy Volunteers Under Fasting Conditions, Ther Drug Monit, 2011;33(3):355–61.
  167. Di Girolamo G, Keller G, de Los Santos A, et al., Bioequivalence of two levothyroxine tablet formulations without and with mathematical adjustment for basal thyroxine levels in healthy Argentinian volunteers: a singledose, randomized, open-label, crossover study, Clin Ther, 2008;30(11):2015 –23.
  168. Yannovits N, Zintzaras E, Pouli A, et al., A bioequivalence study of levothyroxine tablets versus an oral levothyroxine solution in healthy volunteers, Eur J Drug Metab Pharmacokinet, 2006; 31(2):73–8.
  169. Koytchev R, Lauschner R, Bioequivalence study of levothyroxine tablets compared to reference tablets and an oral solution, Arzneimittelforschung, 2004;54(10):680–84.
  170. Blouin R, Clifton G, Adams M, et al., Biopharmaceutical comparison of two levothyroxine sodium products, Clin Pharm, 1989;8(8):588–92.
  171. Dong B, Hauck W, Gambertoglio J, et al., Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism, JAMA, 1997;277(15):1205–13.
  172. Carpi A, Toni M, Maccheroni M, De Gaudio C. Long term therapy with a new liquid L-thyroxine preparation: bioequivalence with L-T4 tablets, Thyroidology, 1992;4(3):115-9.
  173. Ingbar J, Braverman L, Ingbar S, Equivalence of Thyroid Preparations, JAMA, 1980;244(10):1095.
  174. Hansen K, Equivalence of thyroid preparations. JAMA. 1980; 244(10):1095.
  175. Hennessey J, Burman K, Wartofsky L, The equivalency of two L-thyroxine preparations, Ann Intern Med, 1985;102(6):770– 73.
  176. Ramos-Gabatin A, Jacobson J, Young R, In vivocomparison of levothyroxine preparations, JAMA, 1982;247(2):203–5.
  177. Mayor G, Orlando T, Kurtz N, Limitations of levothyroxine bioequivalence evaluation: analysis of an attempted study, Am J Ther, 1995;2(6):417 –32.
  178. Jacobson J, Ramos-Gabatin A, Young R, et al., Nonequality of Brand Name Thyroxine Preparations, JAMA, 1980;243(8):733.
  179. Carpi A, De Gaudio C, Cirigliano G, Toni M, Comparison of the effect of a single oral L-thyroxine dose (150 micrograms) in tablet and in solution on serum thyroxine and TSH concentrations, Thyroidology, 1993;5(1):9–12.
  180. Stoffer S, Szpunar W, Potency of Brand Name and Generic Levothyroxine Products, JAMA, 1980;244(15):1704–5.
  181. Sawin C, Surks M, London M, et al., Oral thyroxine: variation in biologic action and tablet content, Ann Intern Med, 1984;100(5):641–5.
  182. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Levothyroxine Sodium Tablets – In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing, 2000
  183. Blakesley V, Awni W, Locke C, et al., Are bioequivalence studies of levothyroxine formulations in euthyroid volunteers reliable?, Thyroid, 2004;14(3):191–200.
  184. Gibaldi M, Bioequivalence of Thyroid Preparations: The Final Word?, AAPS J, 2005;7(1):E59–60.
  185. U.S. Food and Drug Administration. FDA News: FDA Acts to Ensure Thyroid Drugs Don’t Lose Potency Before Expiration Date, [Online], 2007, accessed 20 December 2012.

Further Resources

Share this Article
Related Content In Thyroid Disorders
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72