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

Edwards, Geoffrey (2003) 'Ivermectin: does P-glycoprotein play a role in neurotoxicity?'. Filaria Journal, Vol 2, Issue Suppl1.

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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Additional Information: Published: 24 October 2003. 6 pages (page numbers not for citation purposes. The electronic version of this article is the complete one and can be found online at:
Uncontrolled Keywords: macrocyclic lactone ivermectin; human filarial infections; onchocerciasis; lymphatic filariasis; albendazole; Onchocerciasis; Loa loa; ivermectin; central nervous system
Subjects: ?? R1 ??
QV Pharmacology > QV 38 Drug action.
QX Parasitology > Helminths. Annelida > QX 301 Filarioidea
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General)
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 885 Onchocerciasis
Digital Object Identifer (DOI):
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Depositing User: Ms Julia Martin
Date Deposited: 07 Jul 2008 10:11
Last Modified: 16 Dec 2020 11:05


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