A dissolution anomaly involving ticrynafen in simulated intestinal fluid without enzyme

Area of Science:

• Pharmacokinetics
• Drug Dissolution
• Medicinal Chemistry

Background:

• Ticrynafen exhibits unusual dissolution patterns in simulated intestinal fluid.
• The presence of potassium ions appears to be a key factor in this anomalous behavior.
• Formation of an insoluble ticrynafen-potassium complex is hypothesized.

Purpose of the Study:

• To investigate the cause of ticrynafen's anomalous dissolution.
• To determine the effect of co-administering ticrynafen with potassium on its bioavailability.
• To assess the clinical relevance of the observed in vitro complex formation.

Main Methods:

• Solubility studies were conducted to analyze ticrynafen-potassium interactions.
• A three-way cross-over study involving 12 human subjects was performed.
• Bioavailability of ticrynafen was measured with and without concomitant potassium supplementation.

Main Results:

• Ticrynafen forms a 1:1 insoluble complex with potassium ions.
• This complex acts as a barrier, preventing complete ticrynafen dissolution in vitro.
• Concomitant administration of ticrynafen and potassium supplements did not negatively affect ticrynafen bioavailability in subjects.

Conclusions:

• The anomalous dissolution of ticrynafen is attributed to potassium ion-induced complex formation.
• Despite in vitro dissolution challenges, co-administration with potassium supplements is safe regarding bioavailability.
• Clinical implications suggest that patients can take ticrynafen with potassium supplements without compromising drug absorption.