What are the mechanisms by which ABCB1 (P‑glycoprotein) dysfunction increases ivermectin neurotoxicity risk?
Executive summary
ABCB1 (P‑glycoprotein, P‑gp) functions as a powerful efflux pump at the blood–brain barrier that normally prevents ivermectin accumulation in the CNS, so loss or inhibition of P‑gp permits large increases in brain ivermectin and thereby raises neurotoxicity risk [1][2]. Animal models and veterinary genetics show dramatic brain accumulation and heightened sensitivity when ABCB1/P‑gp is nonfunctional, while human serious neurological reports are rare and complicated by co‑factors—leaving clear mechanistic plausibility but incomplete human frequency data [1][3][4].
1. P‑glycoprotein at the blood–brain barrier is the frontline defense against ivermectin brain entry
P‑gp (ABCB1/MDR1) is expressed on the luminal membrane of brain capillary endothelial cells where it actively effluxes many lipophilic drugs back into the blood, and ivermectin is a well‑documented substrate of this transporter, explaining its normally minimal brain penetration [5][6][2]. Functional imaging and knockout studies demonstrate that ABCB1 activity, rather than plasma exposure alone, determines brain distribution for P‑gp substrates, meaning the BBB pump is the decisive barrier for ivermectin neuroexposure [7][5].
2. Loss‑of‑function mutations or genetic knockout produce very large increases in brain ivermectin and massive sensitivity
Genetic disruption of Abcb1a in mice led to brain ivermectin levels tens-to-hundreds of times higher than wild type and to 50–100‑fold increases in neurotoxicity in experimental animals, and the same pattern appears in dog breeds homozygous for ABCB1 nonsense mutations such as some collies, which exhibit the ivermectin‑sensitive phenotype [1][7][2]. Transgenic and knockout mouse lines engineered with the canine ABCB1‑1Δ mutation reproduce lethargy, stupor, ataxia and other signs seen in ivermectin‑sensitive dogs, linking genotype to phenotype via altered brain drug handling [8][9].
3. Mechanistic chain from increased brain ivermectin to neural toxicity: binding to GABA(A) receptors
Once ivermectin crosses into the CNS in sufficient concentrations, its primary neurotoxic action is through potentiation of inhibitory GABA(A) receptor pathways and related chloride channels, producing sedation, ataxia, seizures or coma—effects observed in P‑gp‑deficient animals exposed to ivermectin [10][11]. The separation between systemic and brain levels in Abcb1 knockout models (large brain increases with modest plasma changes) underscores that central receptor engagement, not peripheral overdose alone, drives the toxidrome when P‑gp protection fails [7][1].
4. Drug‑drug interactions and transporter competition can mimic genetic loss‑of‑function
Other P‑gp substrates or inhibitors can reduce ivermectin efflux at the BBB or gut and thereby increase brain exposure; experimental data show that coadministered P‑gp interacting drugs alter ivermectin pharmacokinetics across species and that competitive inhibition at the transporter can effectively raise CNS levels [12][5]. Additionally, other transporters such as ABCG2 may interact with ivermectin in a species‑specific way, but their effects can be masked by dominant ABCB1 activity, complicating prediction of interactions [12].
5. Human cases, confounders, and the limits of the evidence
Serious neurological adverse events after ivermectin in humans are uncommon; reported clusters during mass‑drug campaigns have been attributed variously to high Loa loa microfilarial loads, rare ABCB1 variants, or other causes, and firm evidence for common deleterious ABCB1 nonsense mutations in humans is lacking—human case reports exist but frequency and causal attribution remain uncertain [3][4]. Clinical and epidemiologic data therefore support mechanistic plausibility from the animal genetics and transporter biology, but extrapolation to population risk in humans is limited by sparse human genetic and controlled interaction data [4][3].
6. Implications for practice and remaining uncertainties
The convergent animal, veterinary and molecular literature establishes ABCB1/P‑gp dysfunction—whether genetic, pharmacologic, or competitive—as a clear mechanism that allows ivermectin to reach GABAergic targets in the brain and produce neurotoxicity, arguing for caution with known P‑gp inhibitors and attention to breed/genotype in veterinary contexts [1][12][8]. Nonetheless, gaps remain about the prevalence and impact of human ABCB1 loss‑of‑function alleles, the clinical significance of milder polymorphisms, and how co‑infections like Loa loa interact with transporter‑mediated effects, all of which require targeted human pharmacogenetic and clinical studies [4][3].