Drug and fatty acid effects on serum thyroid hormone binding

Area of Science:

• Endocrinology
• Pharmacology
• Biochemistry

Background:

• Thyroid hormone transport in serum is primarily mediated by binding proteins.
• The free fraction of thyroid hormones is biologically active and tightly regulated.
• Certain exogenous substances can displace thyroid hormones from their binding proteins.

Purpose of the Study:

• To directly compare the potency of various drugs and nonesterified fatty acids (NEFA) in displacing thyroxine (T4) from serum binding proteins.
• To understand the factors influencing competitor potency for serum T4 binding.

Main Methods:

• Equilibrium dialysis was used to assess the competitor potency for serum T4 binding.
• Undiluted normal serum was used to avoid artefacts associated with diluted serum or isolated binding proteins.
• Drugs and NEFA were added at concentrations achieving high therapeutic total and free serum levels.

Main Results:

• Fenclofenac, aspirin, meclofenamic acid, diflunisal, mefenamic acid, and furosemide significantly increased the free T4 fraction.
• Diclofenac, flufenamic acid, phenylbutazone, and diphenylhydantoin caused smaller but significant increases in free T4.
• Indomethacin, ketoprofen, tolmetin, ethacrynic acid, bumetanide, iopanoate, and ipodate were inactive.
• Long-chain NEFA, including oleic, arachidonic, linolenic, and linoleic acids, displaced T4, with potency dependent on concentration and protein binding.
• High concentrations of oleic acid significantly inhibited both T3 and T4 binding.

Conclusions:

• Several nonsteroidal anti-inflammatory drugs and long-chain NEFA are potent competitors for serum T4 binding.
• The protein binding of NEFA is a key determinant of their competitor potency.
• These findings help predict which substances may alter serum thyroid hormone binding and availability.