Which drug interactions and genetic variants (MDR‑1) increase central nervous system exposure to ivermectin?
Executive summary
Loss-of-function variants in the MDR1/ABCB1 gene that abolish P‑glycoprotein (P‑gp) efflux markedly increase ivermectin brain penetration, best documented as a 4‑bp deletion in herding‑breed dogs and as rare nonsense mutations in humans [1] [2]. Drugs that inhibit P‑gp or reduce ivermectin clearance—notably strong CYP3A4 inhibitors and other P‑gp blockers—are mechanistically capable of increasing central nervous system (CNS) exposure to ivermectin, although human clinical evidence for clinically important interactions is limited and adverse events appear rare [3] [4].
1. MDR1/ABCB1 genetic variants that raise CNS ivermectin levels: the clear signals from animals and scattered human cases
A homozygous 4‑base‑pair deletion in the canine MDR1 gene produces a truncated, nonfunctional P‑gp that permits ivermectin to accumulate in the brain and causes marked neurotoxicity in collies and related breeds (mydriasis, ataxia, coma) — the mechanism is firmly established by sequencing and phenotype correlation [1] [5] [6]. Knockout and P‑gp–deficient mouse models similarly show dramatically increased brain accumulation of ivermectin relative to wild types, validating that loss of P‑gp function increases CNS exposure [3] [7]. In humans, rare ABCB1 (MDR1) nonsense mutations have been reported in case reports and letters to journals as plausible explanations for unexpectedly severe ivermectin neurotoxicity, implying the same mechanism may operate in people though such mutations appear uncommon [2].
2. Common human MDR1 polymorphisms: subtler effects and population signals
Human MDR1/ABCB1 polymorphisms (for example the 3435C→T allele and other haplotypes) have been associated with altered drug disposition and, in some small studies of ivermectin response, higher variant frequencies in suboptimal responders or in individuals with adverse events — suggesting these variants can change ivermectin pharmacokinetics or tissue distribution, but data are heterogeneous and not definitive for large effects on CNS penetration [8] [9].
3. Drug interactions that can increase CNS ivermectin exposure: P‑gp inhibitors and CYP3A4 inhibitors
Two interacting pharmacologic mechanisms can elevate brain ivermectin: direct inhibition of P‑gp at the blood‑brain barrier (reducing efflux) and inhibition of CYP3A4‑mediated systemic clearance (raising plasma levels and thereby the gradient into brain). Reviews and pharmacovigilance discussions identify concomitant drugs that inhibit CYP3A4, and substances that inhibit P‑gp, as potential contributors to serious neurological adverse events after ivermectin [4] [3] [10].
4. Mechanistic proof from animal and in‑vitro studies supports human plausibility
Cell models and animal knockout studies show ivermectin is a P‑gp substrate and that inhibiting or removing P‑gp increases brain concentrations; studies comparing ivermectin and related avermectins in mdr1a/b knockout mice and P‑gp–deficient CF‑1 mice demonstrate enhanced CNS accumulation when transporter function is lost [3] [7]. These mechanistic data give biological plausibility to drug interactions or genetic loss‑of‑function producing clinically significant CNS exposure in humans [3] [7].
5. Clinical reports, epidemiology and confounders: rare events and competing explanations
Large post‑marketing experience finds serious neurologic events after ivermectin to be uncommon; case series link many such events to high Loa loa microfilarial loads or to co‑medications with CNS effects, and authors urge further study of MDR1 polymorphisms and drug–drug interactions rather than concluding a single dominant cause [4] [10]. Small human genetic studies report haplotypes associated with altered drug disposition in some patients with post‑ivermectin serious adverse events, but the sample sizes are limited and Loa loa infection or high parasite load remains an important alternative mechanism [9] [4].
6. Practical implications, testing and remaining uncertainties
Where risk is highest — veterinary contexts with known breed‑specific MDR1 deletions or clinical situations with unexplained severe reactions — genotyping for ABCB1/MDR1 loss‑of‑function variants is informative and recommended in dogs and can be diagnostically revealing in select human cases, while caution is warranted when combining ivermectin with strong CYP3A4 or P‑gp inhibitors [1] [2] [8]. However, an accurate, population‑level estimate of how much common human MDR1 polymorphisms or specific drug combinations raise brain ivermectin concentrations is not yet established in the available literature; further pharmacokinetic and pharmacogenetic studies are needed [3] [4].