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Pharmacokinetics

Absorption

Bioavailability

Variably absorbed from the GI tract (range: 40–80%).

Extent of absorption is increased in the fasting state and decreased in malabsorption states (e.g., sprue); absorption also may decrease with age.

Absorption is variable following IM administration.

Currently approved levothyroxine preparations should be considered therapeutically inequivalent unless equivalency has been established and noted in the FDA’s Approved Drug Products with Therapeutic Equivalency Evaluations (Orange Book).

Onset

Due to the long half-life, peak therapeutic effects may not be attained for 4–6 weeks.

Food

Infant soybean formula, soybean flour, cotton seed meal, walnuts, and foods containing large amounts of fiber may decrease absorption of levothyroxine.

Distribution

Extent

Thyroid hormones do not readily cross the placenta; however, some transfer does occur, as evidenced by levels in cord blood of athyrotic fetuses being approximately one-third maternal levels.

Minimally distributed into breast milk.

Plasma Protein Binding

Circulating thyroid hormones are >99% bound to plasma proteins, including TBG, thyroxine-binding prealbumin (TBPA), and albumin. Only unbound hormone is metabolically active.

Elimination

Metabolism

T₄ and T₃ are metabolized principally in the liver through sequential deiodination. Approximately 80% of the daily dose of T₄ is deiodinated to yield equal amounts of T₃ and reverse T₃ (rT₃). T₃ and rT₃ are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.

Elimination Route

Primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T₄ is eliminated in the stool. Urinary excretion of T₄ decreases with age.

Half-life

6–7 days for T₄ (3–4 days in hyperthyroidism; 9–10 days in hypothyroidism).

≤ 2 days for T₃.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C). Protect from heat, moisture, and light.

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).

Compatibility

Reconstituted solution should not be admixed with IV infusion solutions.

Parenteral

Solution Compatibility

Actions

• Thyroid hormones (tetraiodothyronine [thyroxine, T₄] and triiodothyronine [T₃]) regulate multiple metabolic processes, including augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates, and lipids.
• Thyroid hormones also play an essential role in normal growth and development and normal maturation of the CNS and bone. The protein anabolic effects of thyroid hormones are essential for normal growth and development.
• The physiologic actions of thyroid hormones are produced predominantly by T₃, most of which (approximately 80%) is derived from T₄ by deiodination in peripheral tissues.
• T₃ is 4 times more potent than T₄. The ratio of T₄ to T₃ in thyroglobulin is 10–20 to 1.