Ivermectin: does P-glycoprotein play a role in neurotoxicity?

Edwards, Geoffrey (2003) Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria Journal, 2 (Suppl ). S8-S8.

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Abstract

The macrocyclic lactone ivermectin (Mectizan®) is widely used for the control of human filarial infections, particularly as a donated product for onchocerciasis and lymphatic filariasis. In the case of control of lymphatic filariasis in Africa, it is used in combination with donated albendazole. In areas co-endemic for Onchocerciasis and Loa loa, serious adverse reactions have been observed in patients with apparently high microfilaria counts of Loa loa. Recent findings suggest that the severe central nervous system side effects seen in various vertebrates following ivermectin treatment may be due to an absence of, or functional deficiency in P-glycoprotein. P-glycoprotein is expressed in the apical membrane of brain capillary epithelial cells and is responsible for limiting the brain penetration of a range of compounds. Toxicity of ivermectin in some collie dogs may be explained by a 4-bp deletion mutation of the mdr1 gene resulting in a frame shift, generating stop codons that prematurely terminate synthesis of P-glycoprotein. Additionally, sub-populations of CF-1 identified as expressing reduced levels of P-glycoprotein exhibit increased toxicity to substrates of this transporter. Furthermore, while the traditional view of drug-drug interactions is alteration in drug clearance mediated through a change in hepatic drug metabolism, some of these changes may arise through competition for binding sites on P-glycoprotein in the blood-brain barrier, resulting in reduced extracellular efflux and enhanced CNS toxicity. In conclusion, P-glycoprotein is an integral component of the human blood brain barrier and plays a central role in limiting drug uptake into the brain. Altered expression or function of p-glycoprotein could conceivably allow elevation of brain concentrations of ivermectin and produce severe neurotoxicity. This might arise through a genetic polymorphism in p-glycoprotein or co-administration of ivermectin with a drug or foodstuff that might inhibit this efflux transporter.

Item Type:	Article
Additional Information:	Published: 24 October 2003. 6 pages (page numbers not for citation purposes).
Uncontrolled Keywords:	macrocyclic lactone ivermectin, human filarial infections, onchocerciasis, lymphatic filariasis, albendazole, Onchocerciasis, Loa loa, ivermectin, central nervous system
Subjects:	?? R1 ??
Divisions:	Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	07 Jul 2008 10:11
Last Modified:	17 Dec 2022 01:41
DOI:	10.1186/1475-2883-2-s1-s8
Publisher's Statement :	Articles with the Open Access logo are immediately and permanently available online. Unrestricted use, distribution and reproduction in any medium is permitted, provided the article is properly cited. See BioMed Central open access charter. http://www.biomedcentral.com/info/about/charter/
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URI:	https://livrepository.liverpool.ac.uk/id/eprint/785