Cyclosporin A and trifluoperazine, two resistance-modulating agents, increase ivermectin neurotoxicity in mice

The P-glycoprotein expressed in the blood-brain barrier has been associated with the restricted access of many compounds to the central nervous system . Mice lacking the mdr1a P-glycoprotein gene show an accumulation of variou s drugs in brain tissues. P-glycoprotein is also correlated with the phenom enon of multidrug resistance in tumour cells. To investigate the effects of drugs that modulate multidrug resistance in the selective permeability of the blood-brain barrier, mice were treated with cyclosporin A or trifluoper azine plus ivermectin, a P-glycoprotein substrate, that has a limited acces s to the central nervous system. When mice received an injection of cyclosp orin A (50 mg/kg, intraperitoneally) or trifluoperazine (750 mu g/kg, intra peritoneally) one hour prior to the administration of ivermectin (10-15 mg/ kg, intraperitoneally) there was an increase in the acute toxicity of iverm ectin. HPLC analysis of brain tissues indicated that the ivermectin brain c oncentration was 2.5 times higher when mice were previously treated with cy closporin A (50 mg/kg). These results suggest that attention should be give n to the side effects of drugs that interact with P-glycoprotein and are co mmonly used clinically and also to the possibility of creating a pharmacolo gical gap in the blood-brain barrier that allows the access of chemotherape utic drugs to brain tumours.