Cyclosporin A and Trifluoperazine, Two Resistance‐Modulating Agents, Increase Ivermectin Neurotoxicity in Mice

Abstract

Ahs/racr: 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 /ndrla 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 pg/kg, intraperitoneally) one hour prior to the administration of ivermectin (10-15 mgikg, 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.

Administration of Drugs Known to Inhibit P-Glycoprotein Increases Brain Bilirubin and Alters the Regional Distribution of Bilirubin in Rat Brain

“…Other studies have also found that inhibition of P-gp increases the brain accumulation of P-gp substrates. In one study the P-gp inhibitor cyclosporin A administered intraperitoneally increased brain concentrations of ivermectin 2.5-fold in adult female rats (31). In an in vivo microdialysis study in freely moving young adult rats, cyclosporin A induced a 3-fold increase in the cortical concentration of rhodamine 123 (32).…”

A Review on the Toxicity and Non-Target Effects of Macrocyclic Lactones in Terrestrial and Aquatic Environments

“…The lack of effect of IVM on the mammalian nervous system at therapeutic concentrations is probably because it is a large molecule. Thus, vertebrates (mostly mammals) are normally protected from the effects of avermectins by the blood-brain barrier [90]. However, although signs of toxicosis have not been observed in collie dogs treated repeatedly with IVM at doses ≤ 60 µg kg -1 of body weight, certain genetic lines of collies (approximately 35% of all collies treated with 120 µg IVM kg -1 ) develop mild to moderate signs of toxicosis [91-92].…”

Review of the pharmacokinetics, interactions and adverse reactions of cyclosporine in people, dogs and cats

“…References: Myre and others (1991), Albengres and Tillement (1992), Lo and others (1997), Omar and others (1997), Dahlinger and others (1998), Ku and others (1998), Lebwohl and others (1998), Caswell (1999), Edwards and others (1999), Marquessantos andothers (1999), McAnulty andLensmeyer (1999), Rosenbaum (1999), Dresser and others (2000), Fugh-Berman (2000), Cather and others (2001), Daigle and others (2001) ACE Angiotensin-converting enzyme topical ocular treatment with 2 per cent cyclosporine (Gilger and others 1995). In human beings cyclosporine is absorbed through the mucous membranes, partly facilitated by saliva, and fiveminute oral 'swish' therapy with 5 ml of 100 mg/ml cyclosporine has been shown to be effective in some immunemediated diseases of the oral mucosa, such as erosive lichen planus (Eisen and Ellis 1990) and cicatrichial pemphigoid (Azana and others 1993).…”