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Ivermectin: does P-glycoprotein play a role in neurotoxicity?
1Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, UK. ge1000@liverpool.ac.uk
Filaria Journal
|February 21, 2004
Summary
Ivermectin neurotoxicity may stem from P-glycoprotein deficiency, affecting drug transport across the blood-brain barrier. Genetic factors or drug interactions can impair this protein, increasing ivermectin
Area of Science:
- Pharmacology
- Neuroscience
- Genetics
Background:
- Ivermectin is crucial for treating filarial diseases like onchocerciasis and lymphatic filariasis.
- Serious adverse reactions, particularly neurotoxicity, have been observed in patients with high Loa loa microfilaria counts.
- P-glycoprotein, a transporter protein, limits drug entry into the brain.
Purpose of the Study:
- To investigate the role of P-glycoprotein in ivermectin-induced neurotoxicity.
- To explore potential genetic and drug-interaction mechanisms underlying ivermectin's adverse effects.
Main Methods:
- Review of existing findings on P-glycoprotein function and ivermectin toxicity.
- Analysis of genetic mutations (e.g., mdr1 gene deletion in collie dogs) affecting P-glycoprotein.
- Examination of drug-drug interactions involving P-glycoprotein.
Main Results:
- Absence or deficiency of functional P-glycoprotein may lead to severe central nervous system side effects from ivermectin.
- A specific gene mutation in collie dogs explains their ivermectin toxicity.
- Reduced P-glycoprotein levels in certain animal models correlate with increased toxicity.
- Drug interactions at the blood-brain barrier, mediated by P-glycoprotein, can enhance CNS toxicity.
Conclusions:
- P-glycoprotein is vital for limiting ivermectin's brain penetration.
- Altered P-glycoprotein expression or function, due to genetic factors or co-administered substances, can elevate brain ivermectin concentrations, causing neurotoxicity.