What are the pharmacokinetics of levothyroxine, including absorption, distribution, metabolism, and excretion?

Pharmacokinetics of Levothyroxine: Absorption, Distribution, Metabolism, and Excretion

Levothyroxine has complex pharmacokinetics characterized by variable absorption from the gastrointestinal tract, high protein binding, extensive metabolism through deiodination, and primarily hepatic elimination with enterohepatic recirculation.

Absorption

• Levothyroxine is absorbed from the gastrointestinal tract, primarily from the jejunum and upper ileum, with absorption ranging from 40% to 80% 1
• The relative bioavailability of levothyroxine tablets compared to oral solution is approximately 93% 1
• Absorption is increased by fasting and decreased by malabsorption syndromes 1
• Several factors can impair levothyroxine absorption:
  • Foods such as soybeans, dietary fiber, grapes, papaya, and coffee 2
  • Medications including proton-pump inhibitors, antacids, and sucralfate 2
  • Gastrointestinal conditions that disrupt intestinal barrier integrity or impair gastric acidity 2
  • Gastrointestinal disorders like ulcerative colitis, celiac disease, gastritis, and Helicobacter pylori infection 3

Distribution

• Circulating thyroid hormones are greater than 99% bound to plasma proteins, including:
  • Thyroxine-binding globulin (TBG)
  • Thyroxine-binding prealbumin (TBPA)
  • Albumin (TBA) 1
• The high affinity of TBG and TBPA for T4 explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3 1
• Only unbound hormone is metabolically active 1
• Many drugs and physiologic conditions can affect the binding of thyroid hormones to serum proteins 1
• Thyroid hormones do not readily cross the placental barrier 1
• Age-related changes in body composition (increased body fat, decreased total body water) can affect plasma concentrations of levothyroxine 4

Metabolism

• Levothyroxine (T4) is primarily metabolized through sequential deiodination 1
• The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at other sites including the kidney 1
• Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination 1
• About 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3) 1
• T3 and rT3 are further deiodinated to diiodothyronine 1
• Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates 1
• Hepatic insufficiency can significantly affect the elimination of thyroid hormones 4
• The half-life of levothyroxine is 6-7 days in euthyroid patients, 3-4 days in hyperthyroidism, and 9-10 days in hypothyroidism 1

Excretion

• Thyroid hormones are primarily eliminated by the kidneys 1
• Conjugated hormone reaches the colon unchanged and is eliminated in the feces 1
• Approximately 20% of T4 is eliminated in the stool 1
• Urinary excretion of T4 decreases with age 1
• Thyroid hormones undergo enterohepatic recirculation after excretion into the bile and gut 1
• Renal insufficiency has a smaller effect on plasma kinetics of thyroid hormones and their metabolites compared to hepatic insufficiency 4

Pharmacokinetic Parameters

• Levothyroxine has a biologic potency of 1 (compared to 4 for liothyronine/T3) 1
• Protein binding is extremely high at 99.96% 1
• The half-life is 6-7 days in euthyroid patients 1
• Levothyroxine demonstrates linear pharmacokinetics at clinically relevant doses 4

Clinical Implications and Considerations

• The high protein binding and long half-life of levothyroxine contribute to its once-daily dosing regimen 1
• Absorption is optimal when taken on an empty stomach, at least 30 minutes before breakfast 5
• Novel formulations like liquid levothyroxine may have improved absorption characteristics, especially in patients with absorption issues 2
• A recent study showed that a novel levothyroxine solution had similar bioavailability whether taken 15 or 30 minutes before a high-fat meal 5
• Therapeutic drug monitoring may be useful when levothyroxine is used with medications that potentially interact with its metabolism 4
• Hypothyroidism may be associated with non-alcoholic fatty liver disease (NAFLD), and levothyroxine replacement may help mobilize hepatic fat 6

Common Pitfalls and Caveats

• Failure to recognize factors that impair levothyroxine absorption can lead to inadequate treatment response 3
• Not accounting for age-related changes in pharmacokinetics may result in inappropriate dosing in elderly patients 4
• Overlooking potential drug interactions, especially with commonly used medications like antacids and proton pump inhibitors 2
• Inadequate consideration of gastrointestinal conditions that may impair absorption 3
• Not recognizing that the therapeutic effect of levothyroxine is predominantly mediated by T3, the majority of which is derived from T4 by deiodination in peripheral tissues 1