Which chemotherapies are most likely to interact pharmacologically with P‑glycoprotein inhibitors like ivermectin?
Executive summary
Ivermectin is both a substrate and inhibitor of P‑glycoprotein (ABCB1/P‑gp), and preclinical work identifies chemotherapies that rely on P‑gp for cellular efflux—most notably taxanes and vinca alkaloids—as those most likely to be pharmacologically affected by co‑administration of P‑gp inhibitors such as ivermectin [1] [2] [3]. Experimental and cell/animal studies report enhanced tumour cell kill and increased toxicity when P‑gp is blocked, but translation to safe, routine clinical combinations remains unproven because no P‑gp inhibitor has been approved for reversing multidrug resistance in cancer [4] [5].
1. Mechanism matters: why P‑gp inhibitors change chemotherapy behaviour
P‑glycoprotein is an ATP‑dependent efflux pump that lowers intracellular concentrations of many cytotoxic drugs; inhibiting P‑gp increases cellular and sometimes central nervous system exposure of its substrates, amplifying both efficacy and toxicity depending on tissue distribution and expression patterns [3] [5]. Ivermectin has been demonstrated in multiple studies to interact with P‑gp: it is actively transported by P‑gp and can inhibit P‑gp function, a dual role that creates the biochemical basis for drug–drug interactions with P‑gp substrate chemotherapies [3] [1].
2. Chemotherapy classes most at risk: taxanes and vinca alkaloids
Preclinical literature repeatedly shows taxanes and vinca alkaloids as P‑gp substrates whose activity is altered by P‑gp inhibition; paclitaxel in particular has been shown to gain potency when combined with ivermectin in resistant ovarian and non‑small cell lung cancer cell models [2] [6], and vinblastine tissue distribution and toxicity are profoundly affected by loss of P‑gp function in animal knockout models [3]. Those data identify paclitaxel and vinblastine (and by extension related agents in the taxane and vinca families) as the chemotherapies most plausibly subject to clinically meaningful interactions with P‑gp inhibitors such as ivermectin [2] [3].
3. Evidence of synergy — and of danger
Laboratory studies report that inhibiting P‑gp can reverse multidrug resistance and increase chemotherapeutic cell killing: ivermectin and other P‑gp inhibitors restored intracellular retention of cytotoxic agents and raised chemosensitivity in MDR models [7] [8] [9]. Conversely, blocking P‑gp can raise drug levels in protected compartments, notably the brain; co‑administration of strong P‑gp inhibitors such as cyclosporin increased ivermectin’s CNS concentrations and neurotoxicity in mice, underscoring the safety trade‑off inherent in P‑gp blockade [10] [5].
4. Clinical reality: promising preclinical signals but little approved guidance
Despite four decades of targeting P‑gp to overcome cancer drug resistance, no P‑gp inhibitors are currently approved for routine clinical use to reverse multidrug resistance, and translation from cell and animal models into safe, effective human regimens has not yet been achieved [4]. That gap means combinations of ivermectin and chemotherapies remain largely experimental: published works document additive or synergistic effects in cell and animal studies (for example, paclitaxel + ivermectin), but definitive clinical trials validating efficacy and establishing safe dosing and monitoring strategies are lacking [2] [6] [4].
5. Practical implications and research caveats
The existing evidence argues that clinicians and researchers should treat taxanes and vinca alkaloids as highest‑priority candidates for P‑gp interaction risk with ivermectin, anticipating both possible restoration of chemosensitivity and an increased risk of systemic or CNS toxicity when P‑gp is inhibited [2] [3] [10]. However, the evidence base is dominated by in vitro and animal studies, and authoritative statements about specific dosing, timing, or safety monitoring in humans cannot be made from the provided sources; careful clinical trials would be required before recommending ivermectin or other P‑gp inhibitors as adjuncts to standard chemotherapy [4] [5].