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Steady-State Serum T3 Concentrations for 48 Hours Following the Oral Administration of a Single Dose of 3,5,3'-Triiodothyronine Sulfate (T3S)

Santini, Ferruccio, Giannetti, Monica, Ricco, Ilaria, Querci, Giorgia, Saponati, Giorgio, Bokor, Daniela, Rivolta, Giovanni, Bussi, Simona +3 more·2014·Endocrine Practice
DOI 10.4158/ep13331.or
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Abstract

Objective Sulfate conjugation of thyroid hormones is an alternate metabolic pathway that facilitates the biliary and urinary excretion of iodothyronines and enhances their deiodination rate, leading to the generation of inactive metabolites. A desulfating pathway reverses this process, and thyromimetic effects have been observed following the parenteral administration of 3,5,3'-triiodothyronine (T3) sulfate (T3S) in rats. The present study investigated whether T3S is absorbed after oral administration in humans and if it represents a source of T3.Methods Twenty-eight hypothyroid patients (7 men and 21 women; mean age, 44 ± 11 years) who had a thyroidectomy for thyroid carcinoma were enrolled. Replacement thyroid hormone therapy was withdrawn (42 days for thyroxine, 14 days for T3) prior to 131I remnant ablation. A single oral dose of 20, 40, 80 (4 patients/group), or 160 μg (16 patients/group) of T3S was administered 3 days before the planned administration of 131I. Blood samples for serum T3S and total T3 (TT3) concentrations were obtained at various times up to 48 hours after T3S administration.Results At all T3S doses, serum T3S concentrations increased, reaching a peak at 2 to 4 hours and progressively returning to basal levels within 8 to 24 hours. The T3S maximum concentration (Cmax) and area under the 0- to 48-hour concentration-time curve (AUC0-48h) were directly and significantly related to the administered dose. An increase in serum TT3 concentration was observed (significant after 1 hour), and the concentration increased further at 2 and 4 hours and then remained steady up to 48 hours after T3S administration. There was a significant direct correlation between the TT3 AUC0-48h and the administered dose of T3S. No changes in serum free thyroxine (T4) concentrations during the entire study period were observed, whereas serum thyroid-stimulating hormone levels increased slightly at 48 hours, but this was not related to the dose of T3S. No adverse events were reported.Conclusion (1) T3S is absorbed following oral administration in hypothyroid humans; (2) after a single oral dose, T3S is converted to T3 in a dose-dependent manner, resulting in steady-state serum T3 concentrations for 48 hours; (3) T3S may represent a new agent in combination with T4 in the therapy of hypothyroidism, if similar conversion of T3S to T3 can be demonstrated in euthyroid patients who are already taking T4.

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  • These findings indicated that patients could convert sufficient amounts of orally administered T3-S into T3; hence, T3-S could potentially be used in the treatment of hypothyroidism to restore T3 levels without major swings in T3 levels.

    “These findings indicated that patients could convert sufficient amounts of orally administered T3-S into T3; hence, T3-S could potentially be used in the treatment of hypothyroidism to restore T3 levels without major swings in T3 levels (61).”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [61]

  • In clinical studies in thyroidectomized individuals given T3-S orally, circulating T3-S reached a peak level between 3 and 4 hours; T3 levels generated through T3-S desulfation increased rapidly in the circulation, with a peak between 2 and 4 hours followed by a variable plateau that lasted for up to 48 hours and depended on the dose of T3-S administered.

    “Next, clinical studies were conducted in thyroidectomized individuals given T3-S orally. Circulating T3-S reached a peak level between 3 and 4 h. At the same time, T3 levels (generated through T3-S desulfation) increased rapidly in the circulation, with a peak between 2 and 4 h that was followed by a variable plateau that lasted for up to 48 h and depended on the dose of T3-S administered.”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [61]

  • In 28 thyroidectomized patients administered T3S orally, serum T3S levels peaked 2 to 4 hours after administration and declined sharply in the next 10 hours, while T3 remained steady but increased in serum for more than 48 hours, with no adverse events observed.

    “Santini et al conducted a study among 28 thyroidectomized patients administered T3S orally (177). Although serum T3S levels peaked 2 to 4 hours after administration and declined sharply in the next 10 hours, the level of its desulfated (by liver) product, T3, remained steady but increased in serum for more than 48 hours. Even more surprisingly, no adverse events were observed.”

    From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [177]

  • Orally administered T3S generates a pharmacokinetic profile in which T3S levels peak and return to baseline within 12 hours, while desulfated serum T3 levels rise and remain elevated for over 48 hours.

    “When T3S is administered orally, this system generates a favorable pharmacokinetic profile: T3S levels peak and return to baseline in 12 h, but (desulfated) serum T3 levels rise and remain high for over 48 h”

    From Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design (2023) · cites this paper as [53]

  • T3S acts as a slow-release preparation, as demonstrated in thyroidectomized humans in 2014.

    “This result is in effect a “slow-release preparation,” as demonstrated in thyroidectomized humans in 2014 (53).”

    From Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design (2023) · cites this paper as [53]

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Authors
Santini, F., Giannetti, M., Ricco, I., Querci, G., Saponati, G., Bokor, D., Rivolta, G., Bussi, S., Braverman, L. E., Vitti, P., & Pinchera, A.
Affiliations
  • University of Pisa (IT)
  • Bracco (Italy) (IT)
  • Boston University (US)
Corresponding author
Santini, Ferruccio
ORCID
Venue
Endocrine Practice
Publisher
Elsevier BV
Published
2014-07
Volume
20
Issue
7
Pages
680-689
ISSN
1530-891X (ISSN-L)
DOI
10.4158/ep13331.or
OpenAlex
W2050323914
Cited by
31
References
28
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 2 · 2016: 2 · 2015: 1 · 2014: 3
FWCI
1.61
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Endocrine Practice (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
oral bioavailability, thyroid hormone metabolism, desulfation, 131I remnant ablation, thyroidectomy, thyroid hormone replacement, dose proportionality, thyroid-stimulating hormone, free thyroxine, rats, human, pharmacokinetics
MeSH terms
Administration, Oral, Adult, Female, Humans, Male, Middle Aged, Time Factors, Triiodothyronine

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