Tuning Caco-2 permeability by cocrystallization: Insights from molecular dynamics simulation

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Physical Chemistry

Background:

• Intestinal permeability is crucial for oral drug absorption.
• Cocrystallization is a potential strategy to enhance drug permeability.
• The underlying mechanisms of cocrystallization-induced permeability enhancement require elucidation.

Purpose of the Study:

• To investigate the effect of cocrystallization on the intestinal permeability of acetazolamide (ACZ).
• To elucidate the molecular mechanism by which p-aminobenzoic acid (PABA) influences ACZ permeability.
• To explore the potential of cocrystal formation for improving oral bioavailability of poorly permeable drugs.

Main Methods:

• Caco-2 cell permeability assay to evaluate intestinal permeability.
• Molecular dynamics simulations to calculate binding strengths with P-glycoprotein (Pgp).
• Preparation and characterization of acetazolamide-p-aminobenzoic acid cocrystals.

Main Results:

• Acetazolamide (ACZ) cocrystallized with p-aminobenzoic acid (PABA) demonstrated enhanced intestinal permeability.
• PABA binding to P-glycoprotein (Pgp) was weakened in the presence of ACZ.
• Molecular dynamics simulations revealed that PABA reduces ACZ binding to Pgp, leading to a lower efflux ratio.

Conclusions:

• Cocrystallization with PABA can significantly enhance the intestinal permeability of ACZ.
• The mechanism involves PABA weakening the interaction between ACZ and the Pgp efflux transporter.
• Cocrystal formation with Pgp inhibitors may improve the oral bioavailability of BCS Class IV drugs.