title: Transport of isometamidium (Samorin) by drug-resistant and drug-sensitive Trypanosoma congolense.
abstract: The uptake kinetics of a 14C-labelled trypanocidal compound isometamidium chloride (Samorin, RMB Animal Health Ltd, UK) was measured in drug-resistant and drug-sensitive Trypanosoma congolense. It was established that drug uptake was significantly more rapid and quantitatively greater in drug-sensitive parasites. There was clear evidence that drug uptake in both the resistant and sensitive trypanosomes was by a specific, receptor-mediated process. This specific drug transport was energy-dependent, being sensitive to metabolic inhibition with SHAM/glycerol. Significant differences in drug transport were observed which could be correlated with resistance to isometamidium. The optimal pH for drug accumulation was lowered in the resistant trypanosomes; this finding, along with an observed change in specificity for the related compound homidium bromide, suggested that the specific receptor for isometamidium is altered in the resistant trypanosomes, possibly resulting in a reduction in drug uptake. In addition to these alterations in drug uptake, efflux of isometamidium also appears to occur in the resistant trypanosomes. Both a reduction in incubation temperature and metabolic inhibition increased the level of trypanosome-associated isometamidium in the resistant parasites. This was in contrast to observations using drug-sensitive parasites. Furthermore, the addition of calcium flux-modulating agents to the incubation medium also resulted in an increase in accumulation by the resistant parasites.
authors.affiliation: Department of Veterinary Physiology, University of Glasgow Veterinary School, Scotland.
authors.forename: I A
authors.initials: IA
authors.lastname: Sutherland
authors.forename: A
authors.initials: A
authors.lastname: Mounsey
authors.forename: P H
authors.initials: PH
authors.lastname: Holmes
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D003891:Desipramine / Q000494:pharmacology; D004351:Drug Resistance / Q000502:physiology; D005990:Glycerol / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010617:Phenanthridines / Q000378:metabolism* / Q000494:pharmacology; D011136:Polysorbates / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D012457:Salicylamides / Q000494:pharmacology; D013696:Temperature; D014344:Trypanocidal Agents / Q000378:metabolism* / Q000494:pharmacology; D014348:Trypanosoma congolense / Q000187:drug effects / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D010617:Phenanthridines; D011136:Polysorbates; D012457:Salicylamides; D014344:Trypanocidal Agents; C000702:isometamidium chloride; C005703:salicylhydroxamic acid; D014700:Verapamil; D005990:Glycerol; D003891:Desipramine; D011224:Prazosin