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Moxidectin toxicity in senescence-accelerated prone and resistant mice
Vanessa K Lee1, Asheesh K Tiwary, Prachi Sharma-Reddy
1Division of Animal Resources, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA. vlee@dar.emory.edu
Comparative Medicine
|July 22, 2009
Summary
Moxidectin, used safely in animals, caused high mortality in specific mouse strains. Topical application led to central nervous system accumulation and toxicosis, not explained by P-glycoprotein levels.
Area of Science:
- Veterinary Pharmacology
- Toxicology
- Animal Models
Background:
- Moxidectin is a safe antiparasitic in various animal species.
- Senescence-accelerated mouse (SAM) strains (SAMP8, SAMR1) showed unexpected mortality after moxidectin treatment.
- Previous studies linked P-glycoprotein deficiency to drug sensitivity in SAM mice.
Purpose of the Study:
- Investigate the mechanism of moxidectin toxicosis in SAMP8 and SAMR1 mice.
- Determine if P-glycoprotein expression predicts moxidectin sensitivity.
- Analyze moxidectin distribution in the brain and serum.
Main Methods:
- Controlled study involving topical moxidectin application (0.015 mg).
- High-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) for drug quantification in brain and serum.
- P-glycoprotein immunohistochemistry on brain sections.
Main Results:
- Brain moxidectin concentrations were significantly higher in SAMP8 (18x) and SAMR1 (14x) mice compared to controls.
- Serum moxidectin levels did not differ significantly among strains.
- P-glycoprotein staining showed no strain-specific differences, indicating it does not predict sensitivity.
- No gross or histologic organ toxicity was observed.
Conclusions:
- Topically applied moxidectin accumulates in the central nervous system (CNS) at standard doses.
- This CNS accumulation leads to toxicosis in SAMP8 and SAMR1 mice.
- P-glycoprotein expression levels do not correlate with moxidectin sensitivity in these mouse models.
