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The influence of diffusional barriers on presystemic gut elimination
P R Gwilt1, S Comer, P R Chaturvedi
1School of Pharmacy, West Virginia University, Morgantown 26506.
Summary
Gut wall drug barriers significantly impact presystemic gut elimination (PGE), affecting how drugs are processed. These barriers can invalidate common methods for assessing drug absorption and metabolism.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Gastrointestinal Physiology
Background:
- Many drugs undergo significant biotransformation within the gut wall or lumen.
- Drug extraction is often higher following oral versus parenteral administration, suggesting varying diffusional clearances.
Purpose of the Study:
- To investigate the impact of diffusional barriers at the blood-mucosa interface on presystemic gut elimination (PGE).
- To evaluate how these barriers affect pharmacokinetic assessments of drug absorption and metabolism.
Main Methods:
- Computer simulation utilizing a physiological pharmacokinetic model.
- Analysis of drug and metabolite pharmacokinetics under varying barrier conditions.
Main Results:
- A diffusional barrier at the blood-mucosa interface enhances PGE.
- Such barriers invalidate standard pharmacokinetic methods used to assess PGE.
- PGE becomes sensitive to alterations in drug binding within the blood.
- Inaccurate assessment of drug absorption occurs if barriers affect metabolites differently than the parent drug.
Conclusions:
- Diffusional barriers in the gut play a critical role in drug disposition.
- Existing pharmacokinetic models and assessment methods may require refinement to account for these barriers.
- Accurate evaluation of oral drug absorption necessitates consideration of barrier-specific effects on both drugs and metabolites.