Systemic interaction between valproic acid and free fatty acids in rhesus monkeys

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Toxicology

Background:

• Valproic acid (VPA) is an anticonvulsant and mood-stabilizing drug.
• Free fatty acids (FFA) can influence drug binding and disposition.
• Understanding drug interactions is crucial for safe and effective VPA therapy.

Purpose of the Study:

• To investigate the systemic interaction between valproic acid (VPA) and elevated free fatty acids (FFA) in rhesus monkeys.
• To elucidate the impact of FFA on VPA pharmacokinetics, including protein binding and clearance.
• To explore the underlying mechanisms of VPA-FFA interaction.

Main Methods:

• Infusion of Intralipid emulsion to elevate plasma FFA levels in eight rhesus monkeys.
• Measurement of plasma FFA and VPA free fraction (fp) levels.
• Assessment of VPA systemic clearance (Cl) and intrinsic clearance (Clint).
• Analysis of urinary excretion of VPA glucuronide.

Main Results:

• Intralipid infusion significantly increased plasma FFA levels (median 102%) and VPA free fraction (median 18%).
• A positive correlation was observed between increased FFA and increased VPA free fraction.
• VPA intrinsic clearance decreased in most cases (median 22%), with reduced VPA glucuronide excretion.
• A significant positive correlation was found between increased FFA and decreased VPA intrinsic clearance.

Conclusions:

• The interaction between VPA and FFA in rhesus monkeys is complex, involving more than simple protein binding displacement.
• Metabolic inhibition, potentially via glucuronidation pathways, plays a significant role in this interaction.
• Elevated FFA levels can reduce VPA's intrinsic clearance, impacting its overall disposition.