Moxidectin has a lower neurotoxic potential but comparable brain penetration in P-glycoprotein-deficient CF-1 mice...

Area of Science:

• Pharmacology
• Neuroscience
• Genetics

Background:

• Anti-parasitic drugs ivermectin (IVM) and moxidectin (MOX) have limited brain penetration due to P-glycoprotein efflux at the blood-brain barrier.
• MDR1 gene mutations, like nt230(del4), impair P-glycoprotein function, increasing drug brain entry and potential neurological toxicity, particularly in certain dog breeds.
• IVM causes neurological toxicity at 0.1 mg/kg in affected dogs, while MOX is tolerated at this dose, suggesting differences in brain penetration or neurotoxic potential.

Purpose of the Study:

• To investigate the differential neurotoxicity of IVM and MOX in P-glycoprotein-deficient mice.
• To compare the absolute brain concentrations of IVM and MOX in these mice.
• To determine if observed toxicity differences are due to brain penetration or inherent neurotoxic potential.

Main Methods:

• IVM and MOX were administered to P-glycoprotein-deficient CF-1 mice.
• Absolute drug concentrations in the brain were measured.
• Drug-induced neurotoxicity was quantified using a rotarod test to assess walking performance.

Main Results:

• At 0.2 mg/kg, brain concentrations of IVM (100.8 pmol/g) and MOX (140.2 pmol/g) were comparable.
• MOX induced equivalent neurotoxicity at a higher dose (1.09 μmol/kg) than IVM (0.40 μmol/kg).
• MOX demonstrated a 2.7-fold lower neurotoxic potential compared to IVM.

Conclusions:

• The lower neurotoxicity of MOX in P-glycoprotein-deficient models is primarily due to its reduced intrinsic neurotoxic potential rather than lower brain penetration.
• MOX may have lower binding affinity or intrinsic activity at relevant central nervous system receptors compared to IVM.
• These findings highlight the importance of considering drug-specific neurotoxic potential when assessing risks associated with P-glycoprotein deficiency.