title: Benznidazole vs benznidazole in multilamellar liposomes: how different they interact with blood components?
abstract: In spite of its widespread use, benznidazole's (BNZ) toxicity and low efficacy remains as major drawbacks that impair successful treatments against Chagas disease. Previously, attempting to increase the selectivity and reduce its toxicity on infected tissues, multilamellar liposomes (MLV) composed of hydrogenated soybean phosphatidylcholine (HSPC): distearoyl-phosphatidylglycerol (DSPG): cholesterol (CHOL) 2:1:2 mol:mol loaded with BNZ (MLV-BNZ) were designed. In this work we compared different properties of MLV-BNZ with those of BNZ. Opposite to other hydrophobic drugs, the results indicated that slight changes of BNZ's association degree to proteins and lipoproteins should not modify the percentage of unbound drug available to exert pharmacological action. On the other hand, when loaded in MLV, BNZ reduced its association to plasma proteins in 45% and became refractory to the sinking effect of blood, dropping 4.5 folds. Additionally, when loaded in MLV, BNZ had higher volume distribution (160 +/- 20 vs 102 +/- 15 ml/kg) and total clearance (35.23 +/- 2.3 vs 21.9 +/- 1.4 ml/h.kg), and lower concentration-time curve (7.23 +/- 0.2 vs 9.16 +/- 0.5 microg.h/ml) than BNZ. Hence, these studies showed that for MLV-BNZ, the amount of BNZ can be substantially increased, from 25 to 70%, being this formulation more rapidly cleared from circulation than free drug; also due to the lower interaction with blood components, lower side effects can be expected.
authors: Laboratorio de Diseño de Estrategias de Targeting de Drogas, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Roque Saenz Peña 180, Bernal, 1876, Buenos Aires, Argentina.
authors: Maria Jose
authors: MJ
authors: Morilla
authors: Maria Jimena
authors: MJ
authors: Prieto
authors: Eder Lilia
authors: EL
authors: Romero
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000187:drug effects*; D004347:Drug Interactions; D006801:Humans; D008074:Lipoproteins / Q000187:drug effects; D008081:Liposomes; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D001798:Blood Proteins; D008074:Lipoproteins; D008081:Liposomes; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C009999:benzonidazole