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

Sanderson, L., Dogruel, M., Rodgers, J. , De Koning, H.P. and Thomas, S.A. (2009) 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. Journal of Pharmacology and Experimental Therapeutics, 329(3), pp. 967-977. (doi:10.1124/jpet.108.149872)

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Abstract

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 [<sup>3</sup>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 [<sup>14</sup>C]sucrose and [3H]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.

Item Type:Articles
Keywords:Blood-brain barrier P-glycoproteins drug targeting pentamidine Sleeping sickness
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry and Rodgers, Dr Jean
Authors: Sanderson, L., Dogruel, M., Rodgers, J., De Koning, H.P., and Thomas, S.A.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Research Group:De Koning
Journal Name:Journal of Pharmacology and Experimental Therapeutics
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0022-3565
ISSN (Online):1521-0103
Published Online:04 March 2009

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