Cytotoxic Interactions Between Cannabidiol and Ionophore Coccidiostats in Feline and Canine Kidney Cell Lines—An In Vitro Study

The use of ionophore coccidiostats—salinomycin (SAL), lasalocid (LAS), monensin (MON), and narasin (NAR)—in animal production raises toxicity concerns in non-target species through feed contamination and because of their narrow safety margins. Cannabidiol (CBD) has antioxidant and cytoprotective properties that may modify the cellular response to ionophore-induced toxicity. This study examined the effect of CBD on the cytotoxicity of SAL, LAS, MON, and NAR in feline (CRFK) and canine (MDCK) kidney cells. Cells were exposed for 72 h to each coccidiostat, alone or in combination with CBD, and assessed using mitochondrial activity (MTT), lysosomal activity (NRU), total protein content (TPC), and membrane integrity (LDH) assays; the interaction was evaluated by isobolographic analysis. Molecular docking of CBD and the ionophores to human VDAC1 (PDB 6TIQ) was performed in AutoDock Vina 1.2.7, both individually and in simultaneous multi-ligand combinations, with β-NADH, VBIT-4, and SW016789 as reference ligands. All four ionophores induced concentration-dependent cytotoxicity, with distinct, compound- and species-specific profiles between CRFK and MDCK cells. CBD co-exposure produced divergent interactions depending on the drug and cell model, ranging from marked cytoprotection to pronounced synergistic potentiation of toxicity, most notably for SAL and LAS in canine cells. The ionophores occupied the N-terminal helix, and cannabidiol occupied a partially overlapping C-terminal region, from which β-NADH displaced it, suggesting a plausible structural basis for the observed interactions. These findings indicate that ionophore nephrotoxic potential and its modulation by CBD are both concentration- and species-dependent, warranting further investigation using additional in vitro and in vivo models.