Thyroxine lipophilicity is dominated by its zwitterionic microspecies

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Physical Chemistry
• Biochemistry

Background:

• Thyroxine is a crucial thyroid hormone with multiple ionization states (microspecies) in solution.
• Understanding the lipophilicity of these microspecies is key to predicting drug behavior.
• Previous studies often assumed non-charged species dominate lipophilicity.

Purpose of the Study:

• To determine species-specific partition coefficients for thyroxine.
• To investigate the role of protonation state versus structural elements in thyroxine lipophilicity.
• To challenge the assumption that non-charged species are always most lipophilic.

Main Methods:

• Combined microspeciation and lipophilicity analysis.
• Mimicking microspecies partition using similar model compounds.
• Calculating correction factors for accurate lipophilicity determination.

Main Results:

• The non-charged thyroxine microspecies is only 2.40 times more lipophilic than its zwitterionic isomer.
• Iodinated aromatic rings, not protonation state, primarily determine thyroxine's lipophilicity.
• The dominant zwitterionic form contributes over 14,500 times more to overall lipophilicity than the non-charged form.

Conclusions:

• The zwitterionic form of thyroxine is significantly more lipophilic than the non-charged form.
• This finding contradicts the common belief that non-charged species dominate passive diffusion into lipophilic environments.
• Lipophilicity profiles should consider species-specific contributions across the entire pH range.