Spatiotemporal Characterization of Sulfasalazine and 5-ASA Pharmacokinetics Using a Noninvasive Intestinal Sampling...

Area of Science:

• Pharmacology
• Gastroenterology
• Microbiome Research

Background:

• Sulfasalazine's efficacy in inflammatory bowel disease is variable due to complex pharmacokinetics and patient-specific microbial metabolism.
• Accurate gastrointestinal drug concentration sampling is challenging, hindering optimization of sulfasalazine therapy.
• Bacterial azo-reduction is crucial for activating sulfasalazine into 5-aminosalicylic acid (5-ASA).

Purpose of the Study:

• To investigate sulfasalazine pharmacokinetics, correlating intestinal and systemic drug concentrations with bacterial metabolic capacity.
• To evaluate the utility of the CapScan® luminal sampling device for region-specific drug concentration analysis.
• To understand the spatial distribution of sulfasalazine and its metabolites within the gastrointestinal tract.

Main Methods:

• 10 healthy volunteers ingested sulfasalazine and CapScan® devices.
• CapScan® samples were retrieved from stool and assigned to intestinal locations via metabolomic and metagenomic profiling.
• Systemic and luminal drug concentrations (sulfasalazine, 5-ASA, N-acetyl-5-ASA) and bacterial gene presence were analyzed.

Main Results:

• Systemic sulfasalazine peaked at 4 hours, while 5-ASA and N-acetyl-5-ASA peaked at 8 hours.
• Sulfasalazine concentration was highest in the proximal small intestine (SI), decreasing distally as 5-ASA and N-acetyl-5-ASA increased.
• 5-ASA plasma concentrations correlated with distal SI concentrations; bacterial azoreductase and acetyltransferase genes were detected in specific GI regions.

Conclusions:

• Spatially distinct luminal concentrations of sulfasalazine and its metabolites were observed.
• A strong correlation exists between distal SI 5-ASA levels and early plasma exposure.
• Luminal sampling holds potential for improving the understanding of drug pharmacokinetics and optimizing oral drug delivery strategies.