A 'rule of unity' for human intestinal absorption.

Area of Science:

• Pharmacokinetics and Drug Design
• Computational Chemistry
• Medicinal Chemistry

Background:

• Predicting passive intestinal absorption is crucial for effective drug design.
• Lipinski's 'rule of 5' is a common but often unreliable predictor of drug absorption.
• Passive intestinal transport is a key factor in oral drug bioavailability.

Purpose of the Study:

• To introduce and validate an alternative predictive model for passive intestinal absorption.
• To compare the predictive accuracy of the proposed 'rule of unity' against Lipinski's 'rule of 5'.
• To assess the performance of both models using human intestinal absorption data.

Main Methods:

• Development of the 'rule of unity' based on theoretical principles of passive transport.
• Utilized a dataset of experimentally determined passive human intestinal absorption for 155 drugs.
• Employed receiver operating characteristic (ROC) plots and McNemar's test for model comparison.

Main Results:

• The 'rule of unity' demonstrates superior predictability compared to Lipinski's 'rule of 5'.
• Lipinski's 'rule of 5' generated twice as many false predictions as the 'rule of unity'.
• Classification of drugs into 'well absorbed' (>50%) and 'poorly absorbed' (<=50%) based on absorption data.

Conclusions:

• The 'rule of unity' offers a more reliable method for predicting passive intestinal drug absorption.
• This new rule provides improved accuracy in drug design and development.
• The findings suggest a potential advancement in computational approaches to drug bioavailability prediction.