The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers.
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 μl · 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.
Pharmaceutical Sciences Research Division, King’s College London, London, United Kingdom.
Sinthujah
S
Jeganathan
Lisa
L
Sanderson
Murat
M
Dogruel
Jean
J
Rodgers
Simon
S
Croft
Sarah A
SA
Thomas
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D001812:Blood-Brain Barrier; D002831:Choroid Plexus / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009547:Nifurtimox / Q000493:pharmacokinetics*; D011485:Protein Binding; D013395:Sucrose / Q000493:pharmacokinetics; D014344:Trypanocidal Agents / Q000493:pharmacokinetics*; D014346:Trypanosoma brucei brucei; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014344:Trypanocidal Agents; D013395:Sucrose; D009547:Nifurtimox