The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers.

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Jeganathan S, Sanderson L, Dogruel M, Rodgers J, Croft S, Thomas SA

The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers.

J Pharmacol Exp Ther. 2011 Feb;336(2):506-15. doi: 10.1124/jpet.110.172981. Epub 2010 Nov 5.

PubMed ID

21057057 [ View in PubMed

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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 mul . min(-1) . g(-1)). In fact, the loss of barrier integrity associated with trypanosome infection failed to change the distribution of [(3)H]nifurtimox to any significant extent, suggesting there is not an effective paracellular barrier for [(3)H]nifurtimox entry into the CNS. Our studies also indicate that [(3)H]nifurtimox is not a substrate for P-glycoprotein, an efflux transporter expressed on the luminal membrane of the BBB. However, there was evidence of [(3)H]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.

DrugBank Data that Cites this Article

Drugs

Nifurtimox

Drug Carriers

Drug	Carrier	Kind	Organism	Pharmacological Action	Actions
Nifurtimox	Serum albumin	Protein	Humans	Unknown	Binder	Details