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Brain penetration of emodepside is increased in P‐glycoprotein‐deficient mice and leads to neurotoxicosis
Author(s) -
Elmshäuser S.,
Straehle L. C.,
Kranz J.,
Krebber R.,
Geyer J.
Publication year - 2015
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/jvp.12149
Subject(s) - penetration (warfare) , glycoprotein , chemistry , p glycoprotein , microbiology and biotechnology , biology , biochemistry , mathematics , operations research , multiple drug resistance , antibiotics
The antiparasitic drug emodepside ( EMO ) is a substrate of the P‐glycoprotein multidrug efflux carrier (P‐gp; syn. MDR 1, ABCB 1), which has an important function in protecting the brain from potentially toxic compounds by functional drug efflux at the blood–brain barrier ( BBB ). Many dogs of the Collie breed and even dogs of many other breeds have a loss‐of‐function 4‐bp deletion mutation in the MDR 1 gene. In these dogs, brain penetration of many P‐gp‐transported drugs is increased and so their therapeutic usage is restricted. To elucidate the role of P‐gp at the BBB for the brain penetration of EMO , we applied EMO at 1 mg/kg to mdr1 ‐deficient ( PGP mut ) and mdr1 ‐intact ( PGP WT ) CF 1 mice. Whereas in the brain of the PGP WT mice, EMO was below the detection level of 10 ng/g, its concentration was at 43.7 ng/g in the PGP mut mice. Furthermore, appearance of neurological toxicity was analyzed in these mice after application of 1 mg/kg EMO using a rotarod setup. In all PGP mut mice, but not in the PGP WT mice, the walking performance on the rotarod was impaired by EMO with clear differences in the degree and duration of neurological toxicity. Some of the mice were completely unable to walk on the rotarod already at 2 h after drug application and showed long‐lasting ataxia over >24 h. Others even showed significantly reduced walking performance, but completely recovered within 1 day. In conclusion, P‐gp restricts brain penetration of EMO and prevents neurological toxicity of this drug in mice.