Thyroid hormone is and secretion is synthesothalamic- regulated axis. Thyrotropin-releasing hormone released from (TRH) othalamusthe hyp secretion yroid-stimulating hormone, of throm the TSH, f pituitary. TSH, inanterior physiologic stimulus for the synthesis and secretion of thyroid hormones, L-thyroxine (T₄) and L-triiodothyronine (T₃), by the thyroid gland. Circulating serum T₃ and T₄ levels exert a feedback effect on both TRH and TSH secretion. When serum T₃ and T₄ levels increase, TRH and TSH secretion decrease. When thyroid hormone levels decrease, TRH and TSH secretion increase.

The mechanisms by which thyroid hormones exert their physiologic actions are not completely understood, but it is thought that their principal effects are exerted through control of DNA transcription and protein synthesis. T₃ and T₄ diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins.

Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone. The metabolic actions of thyroid hormones include augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates and lipids. The protein anabolic effects of thyroid hormones are essential to normal growth and development.

The physiologic actions of thyroid hormones are produced predominately by T₃, the majority of which (approximately 80%) is derived from T₄ by deiodination in peripheral tissues.

Levothyroxine, at doses individualized according to patient response, is effective as replacement or supplemental therapy in hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis.

Levothyroxine is also effective in the suppression of pituitary TSH secretion in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, Hashimoto's thyroiditis, multinodular goiter and, as adjunctive therapy in the management of thyrotropindependent well-differentiated thyroid cancer (see INDICATIONS, PRECAUTIONS , DOSAGE AND ADMINISTRATION ).

Pharmacokinetics

Absorption — Absorption of orally administered T₄ from the gastrointestinal (GI) tract ranges from 40% to 80%. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of LEVOXYL® tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately 98%. T₄ absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybean infant formula. Dietary fiber decreases bioavailability of T₄. Absorption may also decrease with age. In addition, many drugs and foods affect T₄ absorption (see PRECAUTIONS: DRUG INTERACTIONS and Drug-Food Interactions).

Distribution — Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities vary for each hormone. The higher affinity of both TBG and TBPA for T₄ partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T₄ compared to T₃. Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins (see PRECAUTIONS: DRUG INTERACTIONS and Drug-Laboratory Test Interactions). Thyroid hormones do not readily cross the placental barrier (see PRECAUTIONS, Pregnancy).

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