The disposition of sulindac.

Area of Science:

• Pharmacology
• Drug Metabolism
• Gastroenterology

Background:

• Sulindac is a novel non-steroid anti-inflammatory drug (NSAID).
• NSAIDs are associated with gastrointestinal intolerance.
• Understanding sulindac's disposition is crucial for optimizing its therapeutic use.

Purpose of the Study:

• To investigate the absorption, distribution, metabolism, and excretion (ADME) of sulindac in humans.
• To identify the active metabolite of sulindac.
• To elucidate the pharmacokinetic properties of sulindac and its metabolites.

Main Methods:

• Five separate clinical studies involving normal volunteers.
• Material balance studies to assess drug absorption.
• Analysis of plasma and urine samples to determine drug and metabolite concentrations.
• Pharmacokinetic modeling to determine half-life and steady-state levels.

Main Results:

• Approximately 88% of an oral dose of sulindac is absorbed.
• Major biotransformations include oxidation to sulfone and reduction to sulfide.
• The sulfide metabolite is the active form, with an 18.2-hour half-life.
• Twice-daily dosing achieves steady-state plasma levels of the active sulfide.

Conclusions:

• Sulindac's disposition is characterized by significant absorption and conversion to an active sulfide metabolite.
• The pharmacokinetic profile of the active sulfide metabolite supports twice-daily dosing.
• Reversible metabolism and enterohepatic recycling of sulindac may mitigate gastrointestinal side effects.