The Distribution of Nifurtimox Across the Healthy and Trypanosome-Infected Murine Blood-Brain and Blood-Cerebrospinal Fluid Barriers


Jeganathan, S; Sanderson, L; Dogruel, M; Rodgers, J; Croft, S; Thomas, SA; (2011) The Distribution of Nifurtimox Across the Healthy and Trypanosome-Infected Murine Blood-Brain and Blood-Cerebrospinal Fluid Barriers. The Journal of pharmacology and experimental therapeutics, 336 (2). pp. 506-515. ISSN 0022-3565 DOI: https://doi.org/10.1124/jpet.110.172981

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Abstract

Nifurtimox, an antiparasitic drug, is used to treat American trypanosomiasis (Chagas disease) and has shown promise in treating central nervous system (CNS)-stage human African trypanosomiasis (HAT; sleeping sickness). In combination with other antiparasitic drugs, the efficacy of nifurtimox against HAT improves, although why this happens is unclear. Studying how nifurtimox crosses the blood-brain barrier (BBB) and reaches the CNS may clarify this issue and is the focus of this study. To study the interaction of nifurtimox with the blood-CNS interfaces, we used the in situ brain/choroid plexus perfusion technique in healthy and trypanosome-infected mice and the isolated incubated choroid plexus. Results revealed that nifurtimox could cross the healthy and infected blood-brain and blood-cerebrospinal fluid (CSF) barriers (K-in brain parenchyma was 50.8 +/- 9.0 mu l . min(-1) . g(-1)). In fact, the loss of barrier integrity associ-ated with trypanosome infection failed to change the distribution of [H-3] nifurtimox to any significant extent, suggesting there is not an effective paracellular barrier for [H-3]nifurtimox entry into the CNS. Our studies also indicate that [H-3]nifurtimox is not a substrate for P-glycoprotein, an efflux transporter expressed on the luminal membrane of the BBB. However, there was evidence of [H-3]nifurtimox interaction with transporters at both the blood-brain and blood-CSF barriers as demonstrated by cross-competition studies with the other antitrypanosomal agents, eflornithine, suramin, melarsoprol, and pentamidine. Consequently, CNS efficacy may be improved with nifurtimox-pentamidine combinations, but over time may be reduced when nifurtimox is combined with eflornithine, suramin, or melarsoprol.

Item Type: Article
Keywords: GAMBIENSE SLEEPING SICKNESS, DL-ALPHA-DIFLUOROMETHYLORNITHINE, EFLORNITHINE COMBINATION THERAPY, P-GLYCOPROTEIN, FUNCTIONAL-CHARACTERIZATION, AFRICAN TRYPANOSOMIASIS, NERVOUS-SYSTEM, BRUCEI, TRIAL, DRUG, Animals, Blood-Brain Barrier, Choroid Plexus, metabolism, Chromatography, High Pressure Liquid, Male, Mice, Mice, Inbred BALB C, Nifurtimox, pharmacokinetics, P-Glycoprotein, physiology, Protein Binding, Sucrose, pharmacokinetics, Trypanocidal Agents, pharmacokinetics, Trypanosoma brucei brucei, Trypanosomiasis, African, drug therapy, metabolism
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
PubMed ID: 21057057
Web of Science ID: 286309800024
URI: http://researchonline.lshtm.ac.uk/id/eprint/1096

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