How does P‑glycoprotein at the blood–brain barrier influence ivermectin safety in children and animals?
Executive summary
P‑glycoprotein (P‑gp/MDR1) at the blood–brain barrier acts as an active efflux pump that normally prevents ivermectin from accumulating in the central nervous system, and when P‑gp function is absent, reduced, or inhibited, brain concentrations of ivermectin rise and severe neurotoxicity can follow [1] [2]. This protective mechanism is well documented in animal models—collie dogs with an mdr1 deletion and P‑gp knockout mice show marked sensitivity to ivermectin—while species and age differences complicate direct extrapolation to human children [3] [1] [4].
1. How P‑glycoprotein works at the blood–brain barrier and why it matters for ivermectin
P‑glycoprotein is expressed on the luminal/apical membrane of brain capillary endothelial cells and functions as an ATP‑dependent efflux transporter that limits penetration of many xenobiotics into the brain, including ivermectin; this active pumping explains why ivermectin normally has low BBB penetrability and a wide safety margin for the nervous system in many species [3] [2] [1]. When P‑gp expression or function is reduced—whether genetically, developmentally, or pharmacologically—the efflux barrier is weakened and ivermectin can accumulate in brain tissue, producing neurotoxic effects such as ataxia, depression, coma, or death as seen in multiple animal studies [3] [5] [6].
2. Genetic loss of P‑gp: the collie/mdr1 example and knockout mice
A concrete demonstration comes from dogs: a 4‑base‑pair deletion in the canine mdr1 gene produces truncated, nonfunctional P‑gp and explains the classic ivermectin‑sensitive phenotype in some collie populations, where homozygotes develop severe neurotoxicity after normal veterinary doses [3] [1]. Parallel work in mice with targeted mdr1 knockout strains shows dramatically increased brain accumulation of ivermectin and overt neurotoxic and teratogenic signs compared with wild‑type animals, directly linking P‑gp deficiency to risk [3] [5].
3. Drug interactions, inhibitors, and the placenta: ways the barrier can be breached
Co‑administration of P‑gp inhibitors (for example verapamil or cyclosporin A) or other agents that affect P‑gp function increases systemic exposure and brain or fetal transfer of ivermectin in animal models, resulting in enhanced toxicity and altered pharmacokinetics despite similar intravenous clearance—evidence that pharmacologic inhibition of P‑gp can convert a safe dose into a dangerous one [3] [7] [8]. Animal placenta experiments show P‑gp also forms a maternal–fetal barrier, so P‑gp inhibition can raise fetal exposure and teratogenic risk in preclinical studies [7] [8].
4. Species and age differences: why animal signals may not map neatly onto children
While the mechanistic link between P‑gp and ivermectin neurotoxicity is robust in animals, P‑gp expression and activity vary by species and with developmental stage; mice and rats typically express higher BBB P‑gp than humans, and P‑gp activity increases with age in some models, complicating extrapolation from rodent or canine data to human infants and children [4]. The literature therefore warns that genetic or developmental deficits in P‑gp could increase pediatric susceptibility, but direct human evidence is limited and must be interpreted cautiously [4] [1].
5. Ivermectin itself modulates P‑gp and resistance concerns
Ivermectin is both a substrate and a potent inhibitor of P‑gp, and it can induce P‑gp expression in some cell systems via mRNA stabilization, a dynamic that may influence both host toxicity and parasite resistance; overexpression of P‑gp homologues in nematodes is implicated in ivermectin resistance, while host P‑gp induction or inhibition alters drug disposition [9] [10] [5]. This bidirectional interaction creates complex safety and efficacy considerations when ivermectin is used repeatedly, combined with other drugs, or deployed across species.
6. Practical takeaways and limits of the evidence
The consistent animal data establish that intact P‑gp at the BBB is a central determinant of ivermectin safety: loss, immaturity, or pharmacologic blockade of P‑gp raises brain and fetal ivermectin levels and precipitates neurotoxicity [3] [2] [8]. However, the available sources are dominated by animal and in vitro studies and note species/age differences that limit certainty about the exact pediatric risk in humans; explicit human clinical evidence linking common pediatric P‑gp variation to ivermectin neurotoxicity is not provided in these reports and therefore cannot be asserted from this dataset [4] [1].