Pharmacokinetics

Absorption¹

After oral administration of the product to euthyroid fasted dogs, t_max occurred at approximately 2.5-3 hours. Serum half-life of L-thyroxine was approximately 7 hours. Absolute bioavailability was 22%.¹ and relative bioavailability was about twice that of thyroxine as a tablet.¹

Thyroxine bioavailability following a single dose of Leventa solution (20 μg/kg) is superior to thyroxine tablets.¹

Area under the plasma concentration versus time curve of Leventa and conventional thyroxine tablets following oral dosing at 20 µg/kg. The tablets were administered as two doses 12 hours apart.

There was no accumulation of L-thyroxine in serum after repeated oral administration over 14 consecutive days at a dose rate of 40µg/kg/day.

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Concomitant administration of food delays absorption and reduces the extent of absorption from the gastrointestinal tract by approximately 50%.

Protein binding

L-thyroxine is highly protein bound. In a healthy euthyroid dog, approximately 0.15% of total thyroxine is free. Circulating T4 is bound to thyroxine-binding globulin (60%), thyroid-binding prealbumin (17%), albumin (12%) and high density lipoprotein L2 (11%) (Kaptein et al., 1994). Free T4 predicts the amount of T4 available to tissues at equilibrium.

Metabolism and excretion

The major site of thyroxine (T4) metabolism is the liver. The main pathway for the metabolism of T4 is conversion, by deiodination, to the active metabolite triiodothyronine (T3). Further deiodination of T4 and T3 leads to production of inactive metabolites (e.g. T4 sulfate, T4 glucuronide). Excretion is mainly observed via biliary and, to a lesser extent, urinary routes.

In the dog^2,3 exogenous L-thyroxine is largely eliminated from the body 48 hours after intravenous administration of radiolabeled L-thyroxine. Elimination of T4 is in the form of T4, T3 and glucuronide and sulfate metabolites. Metabolites appear rapidly in the bile (approx. 10 minutes after intravenous administration), peak at 1 hour post-administration and then remain constant for the next 6 hours. In total, about 8% of an intravenous dose of L-thyroxine can be recovered from the bile within 6 hours of administration. There is n egligible enterohepatic recirculation of some metabolites. T4 is eliminated in feces (40% of the administered dose) and in urine (41%).

Pharmacodynamics

L-thyroxine is identical in structure and mode of action to the thyroxine (T4) secreted physiologically and present in mammals with a normally functioning thyroid gland. Thyroxine is metabolised mainly to tri-iodothyronine (T3). T4 and T3 have a large variety of biological effects throughout the body. T4 and T3 are also essential for the normal growth and development of the neurological and skeletal systems.

References

1. Le Traon G, Burgaud S & Horspool LJI. (2008) Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Therap 31:95-101.

2. Kaptein EM, Hays MT & Ferguson DC. (1994) Thyroid hormone metabolism. A comparative evaluation. Vet Clin North Am. Small Anim Pract 24:431-466. 1994.

3. Furth ED, Becker DV, Nunez EA & Reid CF. (1968) Thyroxine metabolism in the dog. Endocrinology 82:976-982.

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