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

作者：Janko C; Geyer J^*

来源：Journal of Veterinary Pharmacology and Therapeutics, 2013, 36(3): 275-284.

DOI：10.1111/j.1365-2885.2012.01424.x

The anti-parasitic drugs ivermectin (IVM) and moxidectin (MOX) normally show limited brain penetration in vertebrates because of effective drug efflux at the bloodbrain barrier by P-glycoprotein, encoded by the multi-drug resistance (MDR1) gene. However, dogs with homozygous nt230(del4) mutation in the MDR1 gene do not express a functionally active P-glycoprotein and show increased brain penetration of these drugs, resulting in neurological toxicity to different degrees. Thus, whereas IVM provokes neurological toxicity at 0.1mg/kg, MOX is tolerated at this dosage. To investigate whether this difference is attributable to lower brain penetration of MOX in the absence of P-glycoprotein or to their neurotoxic potential, we applied IVM and MOX to P-glycoprotein-deficient CF-1 mice and comparatively analysed the absolute drug concentrations in the brain. Furthermore, we quantified drug-induced neurotoxicity by measuring the walking performance of the mice on a rotarod setup. We found that at a dosage of 0.2mg/kg, representing 0.23mol/kg IVM and 0.31mol/kg MOX, the absolute drug concentrations in the brain were comparable with 100.8pmol/g and 140.2pmol/g, respectively. However, MOX induced the same degree of neurotoxicosis at the higher dosage of 1.09mol/kg (0.7mg/kg) compared with IVM at 0.40mol/kg (0.35mg/kg), demonstrating the 2.7-fold lower neurotoxic potential of MOX compared to IVM. This could be explained by a lower binding affinity or lower intrinsic activity of MOX at the relevant central nervous system receptors compared with IVM.

• 出版日期2013-6