How do P-glycoprotein and other efflux transporters affect ivermectin entry into the human brain?
Executive summary
P‑glycoprotein (P‑gp, ABCB1/MDR1) at the blood–brain barrier is the primary efflux transporter that prevents ivermectin from accumulating in the central nervous system by actively pumping the drug back into capillary blood, and loss or inhibition of P‑gp markedly raises brain ivermectin levels and neurotoxic risk [1] [2] [3]. Other transporters—members of the multidrug resistance protein (MRP) family and organic anion transporters—are present at the barrier and may contribute, but evidence from animal models shows P‑gp dominates ivermectin exclusion while BCRP appears not to be a major player for this drug [4] [1] [5].
1. P‑glycoprotein: the molecular gatekeeper that limits ivermectin brain entry
Decades of work in rodents and cellular capillary preparations establish that P‑gp sits on the luminal membrane of brain endothelial cells and uses ATP to efflux ivermectin from the endothelial cytoplasm back into blood, producing unexpectedly poor brain penetration for this highly lipophilic drug [3] [4]. Genetic deletion or functional loss of P‑gp in mice causes dramatic increases in brain ivermectin concentrations—reports document brain levels tens to hundreds of times higher in mdr1 (P‑gp) knockout mice—demonstrating causality, not mere correlation [2] [1].
2. Animal genetics and veterinary case studies: human lessons from collies and knockout mice
Veterinary observations of collie and similar dog breeds with homozygous MDR1 mutations provide a natural experiment: animals lacking functional P‑gp accumulate ivermectin in brain and develop lethargy, ataxia, tremors, seizures and coma at doses tolerated by normal animals, mirroring the pharmacokinetic findings in knockout mice and underscoring P‑gp’s protective role [6] [2] [1]. These cross‑species comparisons strengthen the mechanistic interpretation but stop short of proving identical quantitative effects in humans because direct human brain drug measurements are scarce [4].
3. Other transporters and interactions: nuance beyond P‑gp
Molecular profiling identifies MRPs and OATPs at the barrier and experimental work cautions that these transporters could modulate CNS exposure, yet in vivo knockout experiments indicate breast cancer resistance protein (BCRP/ABCG2) does not significantly affect ivermectin brain levels while P‑gp does [4] [1] [5]. Importantly, drugs that inhibit P‑gp or share transporter and metabolic pathways (often CYP3A4 substrates) can increase ivermectin brain uptake, and cases of neurological adverse events after ivermectin have sometimes involved concomitant use of such interacting drugs [7] [3] [8].
4. Clinical reports, neurotoxicity signals, and alternative explanations
While population use of ivermectin for parasitic diseases has an established safety record, clusters of serious neurological events have been reported in mass‑treatment settings and individual case series; debates in the literature weigh whether these reflect direct ivermectin neurotoxicity from altered P‑gp function versus indirect causes such as very high Loa loa microfilarial burdens or compromised blood–brain barrier integrity from illness [7] [9]. The literature explicitly notes limitations in human data—particularly the practical inability to measure brain concentrations in living patients—which constrains definitive attribution of causality [4] [9].
5. Modifiers of P‑gp function: genetics, inhibitors, diet and age
Human ABCB1 polymorphisms, pharmacologic P‑gp inhibitors (including cyclosporine and protease inhibitors), and even non‑drug factors can alter P‑gp expression or function, theoretically raising CNS ivermectin exposure; experimental work in mice and isolated capillaries shows such modulation elevates brain ivermectin and can provoke toxicity, and recent animal studies report unexpected modifiers such as high‑dose vitamins A or E increasing brain ivermectin by multiple‑fold [3] [10] [11]. However, translating these magnitude effects from mice to human risk requires caution because clinical pharmacodynamic thresholds and barrier compensations differ across species [11] [12].
6. Bottom line and evidence gaps
The mechanistic chain is robust: P‑gp actively excludes ivermectin from the brain and its absence or inhibition permits accumulation with neurologic consequences, while other transporters may modulate but are less implicated for ivermectin; nevertheless, human evidence is indirect, reliant on animal genetics, in vitro capillary work, pharmacokinetic inference, and case reports, and therefore uncertainty remains about the frequency and clinical thresholds at which P‑gp perturbation produces harm in humans [1] [3] [7].