Pharmacological properties

The synthetic levothyroxine contained in Jodthyrox is identical in effect with the naturally occurring major hormone secreted by the thyroid. After absorption it is largely bound to plasma proteins, particularly thyroxine-binding globulin (TBG). It passes very gradually into the cells of the body where, after partial conversion to liothyronine (= L-triiodothyronine) it develops the characteristic thyroid hormone effects on development, growth and metabolic systems.
Adequate iodine intake is essential for endogenous synthesis of the thyroid hormones triiodothyronine and levothyroxine and hence also for the normal function and morphology of the thyroid. Furthermore the deficiency of iodide - a major factor in the origin of the goitre - is replaced by potassium iodide.


Pharmacokinetic properties

Following oral administration the onset of action is seen after 3 - 5 days. Approx. 99.97 % of the levothyroxine and approx. 99.70 % of the liothyronine (= L-triiodothyronine) circulates in the plasma bound to plasma proteins. This protein binding is not covalent and so th bound hormone in the plasma is in continuos and very rapid exchange with the fraction of the free hormone. The same applies to levothyroxine which is added to serum. The half-life of levothyroxine is on average 7 days. In hyperthyroidism it is shorter (approx. 6 days) and in hypothyroidism it is longer (approx. 8 days). The volume of distribution amounts to about 10 - 12 l. The liver contains 1/3 of the entire extrathyroidal levothyroxine which is rapidly exchangeable with the levothyroxine in serum. Thyroid hormones are metabolized mainly in the liver, kidneys, brain, and muscles. The metabolites are excreted with urine and feces. The overall metabolid clearance for levothyroxine is about 1.2 l plasma/day.
On account of their high protein binding thyroid hormones only appear in slight quantities in hemodialysate.
The bioavailability of levothyroxine sodium as Euthyrox 100 tablets, taken on an empty stomach was determined to be 79.6 3 %. Absorption of potassium iodide is virtually 100 %.


Preclinical safety data

Acute toxicity:

Levothyroxine has a very slight acute toxicity. In incidents of poisoning (attempts at suicide) in humans, doses of 10 mg levothyroxine were tolerated without complications. In general, serious complications, such as a threat to vital functions (respiration and circulation) need not be anticipated unless coronary heart disease is present.
The acute toxicity of potassium iodide has been investigated after intraperitoneal and oral administration to mice and after oral administration to rats.
In mice the LD50 after intraperitoneal injection was 1.117+30mg/kg of body weight and after oral administration 2.068+140 mg/kg of body weight. In rats the LD50 was 2.779 mg/kg of body weight. Toxicity symptoms were nonspecific in both animals.
All in all potassium iodide can be characterized as a relatively non-toxic substance in short-term use.

Chronic toxicity:

The chronic toxicity of levothyroxine was studied in various animal species (rat, dog). At high doses, signs of hepatopathy, increased occurrence of spontaneous nephroses as well as changes in organ weights were observed in rats. No substantial adverse reactions occurred in dogs. Several cases of sudden cardiac death have been reported in patients with long years of levothyroxine abuse.
Information from subacute and chronic toxicity studies with potassium iodide in animals is not available.

Reproduction toxicity:

Thyroid hormones pass the placenta only in slight, ineffective amounts. After injection of small doses (up to 24 µg) of levothyroxine in chicken embryos the incidence of strophosomia was increased. Ample experience in humans is available on therapy with levothyroxine in all phases of pregnancy: there is no evidence of any toxic effect on the fetuses or of drug-induced malformations.
No information is available on harmful effects on male or female fertility. There have been no indications of any kind in this connection.
Investigations on the influence of increased iodine supply with the diet during pregnancy have been carried out in rabbits, hamsters, minks and pigs. An influence on the size of litters or on the mortality of newborn animals was found in some animal species but not until the concentration of iodine in the diet were 2-3 powers of 10 above the normal iodine content in the feed (rabbits) or when iodine supply was increased by a factor of 4-8 as compared to the normal supply (minks).

Mutagenicity

No information is available on this subject. So far no indications of any kind have become known suggesting damage to the progeny due to changes in the genome caused by thyroid hormones.
Based on investigations in various test systems using potassium iodine in concentrations between 100 µg and 100 mg/l it can be concluded that potassium iodide does not have biologically relevant mutagenic or carcinogenic effects.

Carcinogenicity

No long-term animal studies have been carried out with levothyroxine.