Distribution of suramin, an antitrypanosomal drug, across the blood-brain and blood-cerebrospinal fluid interfaces in wild-type and P-glycoprotein transporter-deficient mice.
Although 60 million people are exposed to human African trypanosomiasis, drug companies have not been interested in developing new drugs due to the lack of financial reward. No new drugs will be available for several years. A clearer understanding of the distribution of existing drugs into the brains of sleeping sickness patients is needed if we are to use the treatments that are available more safely and effectively. This proposal addresses this issue by using established animal models. Using in situ brain perfusion and isolated incubated choroid plexus techniques, we investigated the distribution of [(3)H]suramin into the central nervous systems (CNSs) of male BALB/c, FVB (wild-type), and P-glycoprotein-deficient (Mdr1a/Mdr1b-targeted mutation) mice. There was no difference in the [(3)H]suramin distributions between the three strains of mice. [(3)H]suramin had a distribution similar to that of the vascular marker, [(14)C]sucrose, into the regions of the brain parenchyma that have a blood-brain barrier. However, the association of [(3)H]suramin with the circumventricular organ samples, including the choroid plexus, was higher than that of [(14)C]sucrose. The association of [(3)H]suramin with the choroid plexus was also sensitive to phenylarsine oxide, an inhibitor of endocytosis. The distribution of [(3)H]suramin to the brain was not affected by the presence of other antitrypanosomal drugs or the P-glycoprotein efflux transporter. Overall, the results confirm that [(3)H]suramin would be unlikely to treat the second or CNS stage of sleeping sickness.
Sanderson
Lisa
L
King's College London, Pharmaceutical Sciences Research Division, Guy's Campus, Hodgkin Building, London Bridge, London SE1 1UL, United Kingdom.
Khan
Adil
A
Thomas
Sarah
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001812:Blood-Brain Barrier; D000440:Butanols / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002831:Choroid Plexus / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D066298:In Vitro Techniques; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010477:Perfusion; D011485:Protein Binding; D013498:Suramin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D014344:Trypanocidal Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000440:Butanols; D014344:Trypanocidal Agents; D013498:Suramin