Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship

Area of Science:

• Pharmacology
• Molecular Biology
• Biochemistry

Background:

• P-glycoprotein (P-gp) mediates cellular efflux of many drugs, including macrocyclic lactones (MLs) like ivermectin.
• MLs are vital antiparasitic agents in veterinary and human medicine.
• Understanding ML-P-gp interactions is crucial for optimizing drug efficacy.

Purpose of the Study:

• To investigate the interaction of various MLs with P-gp.
• To determine the impact of ML structure on P-gp inhibition and ATPase activity.
• To elucidate the role of the sugar moiety in ML-P-gp binding.

Main Methods:

• Assessed ML inhibition of rhodamine123 efflux in P-gp overexpressing cells.
• Measured the effect of MLs on P-gp ATPase activity using membrane vesicles.
• Compared the inhibitory potencies of ivermectin, eprinomectin, abamectin, doramectin, selamectin, and moxidectin.

Main Results:

• All tested MLs increased intracellular rhodamine123, indicating P-gp inhibition.
• Moxidectin showed 10-fold lower potency in inhibiting P-gp function compared to other MLs.
• Selamectin and moxidectin were less potent in competing with verapamil for P-gp ATPase activity.

Conclusions:

• The integrity of the sugar moiety in MLs is critical for optimal interaction with P-gp.
• Structure-affinity relationships with P-gp are important for enhancing ML bioavailability.
• This knowledge aids in strategies for reversing multidrug resistance (MDR).