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

Abstract

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.

Alternative schedules of levothyroxine administration

“…20,21 The half-life of levothyroxine is 6.2 days for patients in a euthyroid state or 7.5 days in hypothyroid patients. 22 Current recommendations for administration of levothyroxine, based on the package insert and drug references, suggest that patients take levothyroxine one half to one hour before breakfast and at least four hours before or after taking drugs that interfere with absorption. 23 Waiting a full 60 minutes between levothyroxine administration and the morning meal, compared with waiting a shorter interval, has been associated with a greater effect for some patients, based on assessment of total T 4 or TSH and free triiodothyronine (FT 3 ).…”

MECHANISMS IN ENDOCRINOLOGY: Impact of isolated TSH levels in and out of normal range on different tissues

“…On the other hand, FT 4 was elevated in 30.4% but normal in 69.6% of patients with suppressed TSH levels (67). Variations cannot be explained by low and variable absorption in the intestine (68), dependence on the fasted or sated condition (69), difference in lean body mass (70), or more rapid excretion. The half-life of T 4 is quite long (6-7 days for euthyroid, 9-10 days for hypothyroid, and 3-4 days for hyperthyroid individuals) and enables maintenance of suppressed TSH levels when medication is only taken every other day (71).…”

High Resolution Free Triiodothyronine-Thyrotropin (Ft3-Tsh) Responses to a Single Oral Dose of Liothyronine in Humans: Evidence of Distinct Inter-Individual Differences Unraveled Using an Electrical Network Model

“…The relationship between [FT4] and [T4] remains constant because of protein binding equilibrium mechanisms, which is similar for [FT3] and [T3]. 1 Upon release of T3 into the bloodstream, almost immediate binding to transport proteins results in a miniscule bioavailable concentration of physiologically active [FT3]. Normally, [FT4] is kept to a constant basal level by means of a negative feedback homeostatic control.…”

“…Compared to a half-life of 21 h for triiodothyronine, the prolonged half-life of thyroxine (T4) of about seven days is largely due to its binding to the plasma thyroid hormone-binding proteins thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin. 1 These proteins, which shield the hydrophobic thyroid hormones from their aqueous environment, buffer a stable circulating free T4 (FT4) pool, which is available for cellular uptake. This free fraction of T4 (FT4) is subject to homeostatic control by the hypothalamic-pituitary-thyroid (HPT) axis where T4 is 99.98% bound and FT4 constitutes only 0.02% of the entire circulating T4 pool.…”

“…Synthetic T3 or liothyronine (L-T3) is not routinely used to treat hypothyroidism due to its short half-life and perceived cardiovascular risks. 1 The effects of chronic administration of L-T4 on the HPT axis have been well studied in hypothyroid individuals, 5 but the effects of single doses L-T3 are not well known. Recent studies have been performed in healthy individuals in the context of pharmacokinetic effects or bioequivalence testing, usually over a period of 24 h. 6 In a recent study, 7 the effects on the HPT system of a single sustained release dose of 50 μ g L-T3 (TriThroid®) in 12 healthy persons were investigated.…”