Metal Coordinated Poly-Zinc-Liothyronine Provides Stable Circulating Triiodothyronine Levels in Hypothyroid Rats

Abstract

Background: Liothyronine (LT3) has limited short-term clinical applications, all of which aim at suppressing thyrotropin (TSH) secretion. A more controversial application is chronic administration along with levothyroxine in the treatment of hypothyroidism. Long-term treatment with LT3 is complicated by its unique pharmacokinetics that result in a substantial triiodothyronine (T3) peak in the blood three to four hours after oral dosing. This is a significant problem, given that T3 levels in the blood are normally stable, varying by <10% throughout the day. Methods: A metal coordinated form of LT3 (Zn[T3][H 2 O])n, known as poly-zinc-liothyronine (PZL), was synthesized and loaded into coated gelatin capsules for delivery to the duodenum where sustained release of T3 from PZL occurs. Male Wistar rats were made hypothyroid by feeding on a low iodine diet and water containing 0.05% methimazole for five to six weeks. Rats were given a capsule containing 24 lg/kg PZL or equimolar amounts of LT3. Blood samples were obtained multiple times from the tail vein during the first 16 hours, and processed for T3 and TSH serum levels. Some animals were treated daily for eight days, and blood samples were collected daily. Results: Rats given LT3 exhibited the expected serum T3 peak (about fivefold baseline) at 3.5 hours, followed by a rapid decline, with serum levels almost returning to baseline values by 16 hours. In contrast, serum T3 in PZLtreated rats exhibited about a 30% lower T3 peak at nine hours. Furthermore, the plateau time, that is, the timespan during which the serum T3 concentration is at least half of T3 peak, increased from 4.9 to 7.7 hours in LT3versus PZL-treated rats, respectively. Serum TSH dropped in both groups, but PZL-treated rats exhibited a more gradual decrease, which was delayed by about four hours compared to LT3-treated rats. Chronic treatment with either LT3 or PZL restored growth, lowered serum cholesterol, and stimulated hepatic expression of the Dio1 mRNA and other T3-dependent markers in the central nervous system. Conclusion: Capsules of PZL given orally restore T3-dependent biological effects while exhibiting a reduced and delayed serum T3 peak after dosing, thus providing a longer period of relatively stable serum T3 levels compared to capsules of LT3.

The Swinging Pendulum in Treatment for Hypothyroidism: From (and Toward?) Combination Therapy

“…A slow-release oral form of LT3 was recently developed and applied in hypothyroid rats where it was found to provide stable, normal serum T3 levels (145). Results from human trials with this agent have yet to be determined, but this provides great hope that future high quality, randomized, controlled clinical trials will establish whether steady-dose LT3 + LT4 combination therapy is superior to LT4 monotherapy in terms of its ability to normalize all parameters of thyroid hormone homoeostasis, including tissue markers, mood, and cognition.…”

Sustained Release T3 Therapy: Animal Models and Translational Applications

“…For example, rodents secrete relatively more T3 from the thyroid gland (about 40% of the daily production rate) and exhibit an approximately 12–24 times faster turnover rate for both serum T4 and T3 (2). However, when focusing on the absorption kinetics, rodents exhibit a similar PK profile as humans, i.e., a serum peak at 3 h after dosing that is followed by a fast decline in its circulating levels (38).…”

“…Poly-Zinc-Liothyronine (PZL) is a copolymer of zinc and T3 that forms a supramolecular complex (Figure 2). These supramolecular complexes of the form [M(T3)] n have superior mucoadhesive properties, and when coupled with the hydrolysis behavior of [M(T3)] n complexes, translate into a slow release formulation of LT3 (38). The properties of a controlled release, orally delivered drug product via metal coordination of a drug ligand, relies on known principles of mucoadhesion and coordination chemistry (49).…”

“…Capsules of PZL were tested in hypothyroid rats via oral gavage, with a significant modification in PK properties (38). After PZL administration serum T3 exhibited about 30% lower peak (lower Cmax) that was delayed (longer Tmax) by about 6h as compared to rats given equimolar amounts of LT3.…”

“…TSH levels, which were elevated, declined rapidly after LT3 administration but in PZL-treated rats the decline was delayed by about 4 h (Figure 5). Daily administration of PZL for 8 days showed that PZL and LT3 had similar long-term biological effects such as reduction of serum cholesterol, restauration of growth rate and induction of T3-dependent genes in the heart, liver and brain (38).…”