Pentamidine movement across the murine blood-brain and blood-cerebrospinal fluid barriers: effect of trypanosome infection, combination therapy, P-glycoprotein, and multidrug resistance-associated protein.
During the first stage of human African trypanosomiasis (HAT), Trypanosoma brucei gambiense is found mainly in the blood, and pentamidine treatment is used. Pentamidine is predominantly ineffective once the parasites have invaded the central nervous system (CNS). This lack of efficacy is thought to be due to the inability of pentamidine to cross the blood-brain barrier, although this has never been explored directly. This study addresses this using brain perfusion in healthy mice, P-glycoprotein-deficient mice, and in a murine model of HAT (T. brucei brucei). The influence of additional antitrypanosomal drugs on pentamidine delivery to the CNS also was investigated. Results revealed that [(3)H]pentamidine can cross the blood-brain barrier, although a proportion was retained by the capillary endothelium and failed to reach the healthy or trypanosome-infected brain (up to day 21 p.i.). The CNS distribution of pentamidine was increased in the final (possibly terminal) stage of trypanosome infection, partly because of loss of barrier integrity (days 28-35 p.i.) as measured by [(14)C]sucrose and [(3)H]suramin. Furthermore, pentamidine distribution to the CNS involved influx and efflux [via P-glycoprotein and multidrug resistance-associated protein (MRP)] transporters and was affected by the other antitrypanosomal agents, suramin, melarsoprol, and nifurtimox, but not eflornithine. These interactions could contribute to side effects or lead to the development of parasite resistance to the drugs. Thus, great care must be taken when designing drug combinations containing pentamidine or other diamidine analogs. However, coadministration of P-glycoprotein and/or MRP inhibitors with pentamidine or other diamidines might provide a means of improving efficacy against CNS stage HAT.
Sanderson
Lisa
L
King's College London, Pharmaceutical Sciences Research Division, Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
Dogruel
Murat
M
Rodgers
Jean
J
De Koning
Harry Pieter
HP
Thomas
Sarah Ann
SA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000225:Adenine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004195:Disease Models, Animal; D004347:Drug Interactions; D000518:Eflornithine / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008549:Melarsoprol / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009547:Nifurtimox / Q000494:pharmacology; D010419:Pentamidine / Q000378:metabolism*; D010477:Perfusion; D013498:Suramin / Q000378:metabolism / Q000494:pharmacology; D014346:Trypanosoma brucei brucei; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000378:metabolism*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000225:Adenine; D000241:Adenosine; D000518:Eflornithine; D007213:Indomethacin; D008549:Melarsoprol; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009547:Nifurtimox; D010419:Pentamidine; D013498:Suramin