What happens if Lipinski's Rule of Five is not met?

• A. Very High Absorption Is Likely
• B. Poor Absorption Is More Likely
• C. Increased Half-Life
• D. Guaranteed Efficacy

Answer: (B)

Lipinski's Rule of Five is a practical guideline for oral bioavailability. It suggests that an orally active drug tends to have a molecular weight under 500 Da, a logP under 5, no more than 5 hydrogen bond donors, and no more than 10 hydrogen bond acceptors. If these rules aren’t met, the molecule is more likely to have poor permeability across intestinal membranes, leading to poor absorption after oral administration. The reasons are that higher molecular weight, greater lipophilicity, or excessive hydrogen bonding can hinder passive diffusion and solubility, reducing the fraction that reaches systemic circulation. So, poor absorption is more likely when Lipinski's criteria aren't satisfied. Increased half-life and guaranteed efficacy aren’t direct implications of these rules, since metabolism/clearance and pharmacodynamics largely determine those outcomes, and there can be exceptions due to transport mechanisms or formulation.