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 various drugs in brain tissues. P-glycoprotein is also correlated with the phenomenon 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 trifluoperazine plus ivermectin, a P-glycoprotein substrate, that has a limited access to the central nervous system. When mice received an injection of cyclosporin A (50 mg/kg, intraperitoneally) or trifluoperazine (750 microg/kg, intraperitoneally) one hour prior to the administration of ivermectin (10-15 mg/kg, intraperitoneally) there was an increase in the acute toxicity of ivermectin. HPLC analysis of brain tissues indicated that the ivermectin brain concentration was 2.5 times higher when mice were previously treated with cyclosporin A (50 mg/kg). These results suggest that attention should be given to the side effects of drugs that interact with P-glycoprotein and are commonly used clinically and also to the possibility of creating a pharmacological gap in the blood-brain barrier that allows the access of chemotherapeutic drugs to brain tumours.
Marques-Santos
L F
LF
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, National Institute of Câncer, INCA, RJ, Brazil. lfmarques@bioqmed.ufrj.br
Bernardo
R R
RR
de Paula
E F
EF
Rumjanek
V M
VM
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005260:Female; D007559:Ivermectin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D051379:Mice; D013997:Time Factors; D014268:Trifluoperazine / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D014268:Trifluoperazine; D007559:Ivermectin; D016572:Cyclosporine