Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.     Pharmacodynamic properties
Pharmacotherapeutic group: thyroid hormones, ATC code: H03AA01
Mechanism of action
Thyroid hormones exert their physiological effects via the control of DNA transcription and protein synthesis.
Triiodothyronine (T3) is diffused in the nucleus of the cell and binds to protein thyroid receptors bound to the DNA. This hormone-receptor complex present in the nucleus activates genetic transcription and synthesis of messenger RNA and cytoplasmic proteins. The physiological effects of thyroid hormones are mainly due to T3, predominantly derived (around 80%) from T4 by deiodination in the peripheral tissues.
Pharmacodynamic effects
The primary pharmacodynamic response to levothyroxine, solution for injection/ Concentrate for solution for infusion, has been the subject of studies in patients with myxedema coma or hypothyroidism, which have demonstrated the capacity of intravenous levothyroxine to increase blood concentrations of T4 and simultaneously reduce TSH levels in these types of patients.
The secondary pharmacokinetic response has been the subject of in vitro studies, which highlighted binding sites shared by levothyroxine and oestradiol 17β-glucuronide (E217βG), a conjugated sterol, in the OATP 1C1 blood- brain barrier transporters, suggesting competition between levothyroxine and other substances when crossing the blood-brain barrier.

Pharmacokinetic Properties

5.2.     Pharmacokinetic properties
Absorption
After parenteral administration, synthetic levothyroxine cannot be differentiated from the natural hormone secreted endogenously.
Distribution
Over 99% of circulating thyroid hormones are bound to plasma proteins, in particular to thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA) and albumin, whose binding capacities and affinities vary depending on the hormones. Thyroid hormones bound to plasma proteins remain inversely correlated with low free hormone concentrations. Only the latter are metabolically active.
Following intravenous administration, the distribution volume is estimated to be 11.6 litres in healthy subjects and 14.7 litres in patients with hypothyroidism.
Biotransformation
The main metabolic pathway for thyroid hormones is sequential deiodination. Around 80% of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the main site for the degradation of T4 and T3, with deiodination of T4 also occurring in a certain number of other sites, in particular the kidneys and other tissues. Around 80% of T4 daily dose is deiodinised to obtain equal quantities of T3 and rT3 (reverse T3). T3 and rT3 are then deiodinised and turn into diiodothyronine (T2). Thyroid hormones are also metabolised by conjugation with sulfate and glucuronic acid and directly excreted in the bile and intestine where they undergo entero-hepatic recirculation.
Elimination
Levothyroxine clearance is estimated to be around 0.050 litres/hour in euthyroid patients; it is slightly higher (0.053 litres/hour) in hypothyroid patients. The elimination half-life of levothyroxine is estimated to be 6 to 7 days in healthy subjects and 9 to 10 days in patients with myxedema coma.