Apomorphine and its esters: Differences in Caco-2 cell permeability and chylomicron affinity

Area of Science:

• Pharmacology
• Drug Delivery
• Biochemistry

Background:

• Oral apomorphine is a potential Parkinson's disease treatment.
• Prodrug strategies are explored to enhance oral bioavailability.
• Apomorphine esters are investigated for improved drug delivery.

Purpose of the Study:

• To evaluate the intestinal transport and stability of apomorphine esters.
• To assess the affinity of apomorphine and its esters towards chylomicrons.
• To understand the molecular basis of ester stability and hydrolysis.

Main Methods:

• Caco-2 cell monolayer model for intestinal permeability studies.
• In vitro stability assays at different pH conditions.
• Molecular dynamics simulations for ester stability analysis.
• Chylomicron affinity assessment.

Main Results:

• Intact dilauroyl apomorphine (DLA) showed significantly lower transport (150-fold reduction) compared to apomorphine.
• Monolauroyl apomorphine (MLA) exhibited high instability, leading to apomorphine release.
• Molecular dynamics simulations provided insights into differential ester hydrolysis.
• Apomorphine diesters demonstrated affinity for chylomicrons, suggesting potential lymphatic transport.

Conclusions:

• Intact DLA transport across the intestinal barrier is unfavorable.
• The conversion of DLA to MLA is a critical step for intestinal apomorphine absorption.
• Understanding ester stability and chylomicron interaction is key for optimizing oral apomorphine prodrugs.