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Intestinal Secretion Is a Potentially Important Clearance Mechanism for Low Metabolic Clearance Compounds.
Murali Subramanian1, Deepak Ahire1, Rakshit Tanna1
1Drug Metabolism, Gilead Sciences Inc, Foster City, California 94404, United States.
Journal of Medicinal Chemistry
|May 25, 2025
Summary
Intestinal excretion (IE) is often overlooked but can be a significant clearance pathway for drugs with low systemic clearance. This study highlights IE
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Drug Excretion
Background:
- Intestinal excretion/secretion (IE) is traditionally viewed as a minor drug clearance pathway.
- Understanding alternative excretion routes is crucial for accurate pharmacokinetic profiling.
Purpose of the Study:
- To investigate the significance of intestinal excretion/secretion (IE) as a drug clearance pathway.
- To identify factors influencing the extent of intestinal excretion.
Main Methods:
- Analysis of 91 pharmacokinetic studies involving intravenous drug administration in bile duct-cannulated animals.
- Quantification of parent drug in feces to assess intestinal excretion.
- Calculation of intestinal excretion extraction ratio (E_IE).
Main Results:
- 15% of compounds showed >20% of the dose excreted in feces via IE.
- 11% of compounds had an IE extraction ratio > 0.05.
- Low systemic clearance, moderate-to-high plasma binding, and low biliary excretion correlated with higher IE.
Conclusions:
- Intestinal excretion/secretion is a significant clearance route for low-clearance molecules.
- IE should be considered in drug development, especially for compounds with specific physicochemical properties.
- Further research into intestinal transporter roles in IE is warranted.
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