When barriers ignore the "rule-of-five"

Area of Science:

• Pharmacokinetics
• Drug Discovery
• Biophysics

Background:

• The oral absorption of drugs that violate Lipinski's rule of 5 (bRo5) is poorly understood.
• Investigating the mechanisms of intestinal absorption for bRo5 compounds is crucial for developing new therapeutics.

Purpose of the Study:

• To determine if bRo5 compounds are absorbed via passive lipid bilayer permeation or carrier-mediated transport.
• To elucidate the physicochemical properties that enable intestinal absorption of certain bRo5 drugs.

Main Methods:

• Experimental studies using liposomes to assess drug permeation.
• Analysis of published experimental data and molecular dynamics simulations.

Main Results:

• Tetracycline and rifampicin, both bRo5 compounds, demonstrated significant permeation of phospholipid bilayers.
• Permeation kinetics were comparable to known drugs like labetalol and metoprolol.
• Intramolecular H-bonds, adoption of elongated shapes, and a significant neutral species fraction facilitate lipid bilayer permeation.

Conclusions:

• Certain bRo5 drugs can permeate the intestinal lipid bilayer via passive diffusion.
• Understanding these mechanisms can guide the design of orally absorbed bRo5 drugs.
• Targeting carrier proteins is an alternative but carries risks of drug interactions and non-linear pharmacokinetics.