Pharmacokinetics

The L-thyroxine in Leventa® solution is identical in structure and mode of action to the thyroxine (T4) in mammals with a functioning thyroid gland. The information presented below is a summary of data on the absorption, distribution, metabolism and excretion from studies performed during the development of Leventa® solution supported by published data on thyroid gland physiology in mammals.


Absorption

  • L-thyroxine, administered orally as Leventa® solution at a dose rate of 40 μg L-thyroxine/kg bodyweight to fasted dogs, is absorbed rapidly from the gastrointestinal tract (tmax approximately 2.5 hours), and reaches maximal serum concentrations of approximately 80 nmol/L.
  • The bioavailability of L-thyroxine, following oral administration of Leventa® solution to dogs, is 22±5.2%.
  • The extent of absorption of L-thyroxine as Leventa® solution is influenced by the feeding status of the dog. The relative bioavailability of L-thyroxine, administered orally as Leventa® solution to dogs that had been fed, was 55%.
  • Repeated oral administration of Leventa® solution (40 μg/kg bodyweight once daily for 14 days) to dogs does not lead to accumulation of L-thyroxine in serum.

Distribution
Following intravenous administration of radiolabeled L-thyroxine to dogs (Kaptein et al., 1994),

  • T4 passes rapidly from plasma to interstitial fluid.
  • the majority of the T4 remains extracellularly for the first 4 hours following administration
  • 40% of the dose can be recovered from intracellular fluid by 15 hours post-administration.
  • tissues can be divided into two categories based on the distribution of T4:
    • rapidly equilibrating tissues (liver, kidney) where more than 90% of the T4 is present intracellularly, and
    • slowly equilibrating tissues (muscle, skin, fat) where most of the T4 is in the interstitial fluid.


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


Metabolism and excretion
T4 is mainly metabolized into active T3 or inactive rT3 in the liver. Several minor metabolites are found, including inactive T4 sulfate, sulphated T4 and glucuronidated T4.
In the dog (Furth et al., 1968, Kaptein et al., 1994),

  • 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 negligible enterohepatic recirculation of some metabolites
  • T4 is eliminated in feces (40% of the administered dose) and in urine (41%).


References
Furth, E. D., Becker, D. V., Nunez, E. A., Reid, C. F. Thyroxine metabolism in the dog. Endocrinology 82(5), 976-982. 1968. (Ref. 6)


Kaptein, E. M., Hays, M. T., Ferguson, D. C. Thyroid hormone metabolism. A comparative evaluation. The Veterinary Clinics Of North America.Small Animal Practice 24(3), 431-466. 1994. (Ref. 10)