Time-dependent effects on small intestinal transport by absorption-modifying excipients.

Area of Science:

• Pharmacokinetics and Drug Delivery
• Gastrointestinal Physiology
• Biomaterials Science

Background:

• The rat single-pass intestinal perfusion model's utility for assessing time-dependent absorption-modifying excipient (AME) effects is not well-defined.
• Understanding AME dynamics is crucial for optimizing oral drug delivery systems.

Purpose of the Study:

• To evaluate the dynamic effects and recovery of intestinal mucosa following exposure to AMEs.
• To assess the time-dependent impact of sodium dodecyl sulfate (SDS) and chitosan on drug absorption and intestinal function.

Main Methods:

• Utilized the rat single-pass intestinal perfusion model to measure lumen-to-blood flux (Jabs) of model compounds and blood-to-lumen clearance of 51Cr-EDTA (CLCr).
• Investigated 15- and 60-minute mucosal exposures to SDS and chitosan, with and without mecamylamine to assess neural contributions.
• Analyzed Jabs and CLCr to determine the time- and concentration-dependent effects of AMEs and mucosal recovery.

Main Results:

• Increased Jabs and CLCr were dependent on AME exposure time and SDS concentration, but not chitosan concentration.
• Short (15-min) AME exposures showed greater absorption enhancement than in vivo bolus models, predictable by a six-fold Jabs increase.
• Mucosal recovery was complete after 15-min exposures but only 50% after 60-min exposures; Jabs was more sensitive than CLCr for detecting AME effects.

Conclusions:

• The rat single-pass intestinal perfusion model is relevant for studying time-dependent AME effects and mucosal recovery.
• Rapid and robust AME effects are critical for enhancing in vivo intestinal absorption before drug transit.
• No significant nicotinergic neural contribution was observed for SDS or chitosan absorption enhancement.