Fumagillin, a new P-glycoprotein-interfering agent able to modulate moxidectin efflux in rat hepatocytes

Area of Science:

• Pharmacology
• Drug Metabolism
• Veterinary Medicine

Background:

• Moxidectin is a macrocyclic lactone (ML) used in veterinary medicine.
• P-glycoprotein (P-gp) is an efflux pump that can limit drug efficacy.
• Optimizing intracellular drug concentrations is crucial for therapeutic success.

Purpose of the Study:

• To evaluate the ability of veterinary drugs fumagillin and diminazene diaceturate to increase intracellular moxidectin.
• To investigate the interference of these drugs with P-glycoprotein (P-gp) function.

Main Methods:

• Cultured rat hepatocytes were used to measure intracellular 14C-moxidectin.
• Porcine kidney epithelial cells (Mdr1a-LLCPK1) expressing murine P-gp were used to assess P-gp function.
• Rhodamine 123 (Rho 123) accumulation was measured as a functional P-gp assay.

Main Results:

• Both fumagillin and diminazene diaceturate significantly increased intracellular moxidectin concentrations.
• Fumagillin, but not diminazene diaceturate, markedly inhibited P-gp function, indicated by Rho 123 accumulation.
• Fumagillin's EC50 for P-gp inhibition was 34 microm.

Conclusions:

• Fumagillin and diminazene diaceturate can enhance intracellular moxidectin levels in hepatocytes.
• Fumagillin's interaction with P-gp suggests it may optimize the therapeutic use of macrocyclic lactones (MLs).
• Further research into fumagillin for P-gp inhibition could improve ML drug efficacy.