Distribution of Levothyroxine: Pharmacokinetic Profile
Protein Binding Characteristics
Levothyroxine exhibits extremely high protein binding at greater than 99% in circulation, primarily bound to three plasma proteins: thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA). 1
- TBG and TBPA demonstrate higher affinity for T4 (levothyroxine) compared to T3, which partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 (6-7 days in euthyroid patients) compared to T3 (≤2 days) 1
- The capacities and affinities of these binding proteins vary for each thyroid hormone 1
- Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone 1
Active vs. Bound Hormone
- Only the unbound (free) hormone fraction is metabolically active, despite the vast majority being protein-bound 1
- The free hormone represents less than 0.04% of circulating T4 (99.96% is protein-bound) 1
Factors Affecting Distribution
Many drugs and physiologic conditions can significantly alter the binding of thyroid hormones to serum proteins, thereby affecting distribution and bioavailability. 1
- Medications that interfere with protein binding or absorption can necessitate higher levothyroxine doses, with approximately 21% of patients requiring high doses due to medication interference 2
- Conditions affecting gastrointestinal absorption (such as celiac disease, atrophic gastritis) can impair bioavailability, with studies showing that 4 newly diagnosed celiac disease patients required dose reductions after treatment of their underlying condition 2
Tissue Distribution
- Levothyroxine diffuses into cell nuclei where it binds to thyroid receptor proteins attached to DNA, activating gene transcription 1
- The liver serves as the major site of degradation for T4, though deiodination also occurs in the kidney and other tissues 1
- Approximately 80% of circulating T3 (the active form) is derived from peripheral T4 by monodeiodination in tissues 1
Placental Transfer
- Thyroid hormones do not readily cross the placental barrier, which is clinically significant for pregnant women requiring levothyroxine therapy 1
- Levothyroxine dosage requirements increase during early pregnancy, necessitating dose adjustments for proper fetal neurologic development 3
Clinical Implications of Distribution
- The extensive protein binding creates a large reservoir of hormone, contributing to the long half-life of 6-7 days in euthyroid patients (extending to 9-10 days in hypothyroidism and shortening to 3-4 days in hyperthyroidism) 1
- This distribution pattern explains why steady-state levels are not achieved until 4-6 weeks after dose changes, requiring this interval before reassessing thyroid function tests 4