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Moxidectin has a lower neurotoxic potential but comparable brain penetration in P‐glycoprotein‐deficient CF‐1 mice compared to ivermectin
Author(s) -
JANKO C.,
GEYER J.
Publication year - 2013
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/j.1365-2885.2012.01424.x
Subject(s) - moxidectin , p glycoprotein , pharmacology , ivermectin , mox fuel , neurotoxicity , toxicity , chemistry , pharmacokinetics , efflux , blood–brain barrier , medicine , biochemistry , central nervous system , radiochemistry , multiple drug resistance , plutonium , veterinary medicine , antibiotics
The anti‐parasitic drugs ivermectin (IVM) and moxidectin (MOX) normally show limited brain penetration in vertebrates because of effective drug efflux at the blood–brain 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 0.1 mg/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 0.2 mg/kg, representing 0.23 μmol/kg IVM and 0.31 μmol/kg MOX, the absolute drug concentrations in the brain were comparable with 100.8 pmol/g and 140.2 pmol/g, respectively. However, MOX induced the same degree of neurotoxicosis at the higher dosage of 1.09 μmol/kg (0.7 mg/kg) compared with IVM at 0.40 μmol/kg (0.35 mg/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.