Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method

• Published in: Antimicrobial Agents and Chemotherapy Vol. 56; no. 6; pp. 3344 - 3348
• Main Authors: Moreira da Silva, Rodrigo, Oliveira, Líliam Teixeira, Silva Barcellos, Neila Márcia, de Souza, Jacqueline, de Lana, Marta
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01-06-2012
• Subjects: administered dose; Analytical Procedures; animal models; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; blood serum; Chagas Disease; Chagas Disease - blood; Chagas Disease - drug therapy; chemotherapy; Chromatography, High Pressure Liquid; combination drug therapy; Female; half life; high performance liquid chromatography; Human protozoal diseases; Infectious diseases; Itraconazole; Itraconazole - pharmacokinetics; Itraconazole - therapeutic use; Medical sciences; Mice; monitoring; Nitroimidazoles; Nitroimidazoles - pharmacokinetics; Nitroimidazoles - therapeutic use; Parasitic diseases; pharmacokinetics; Pharmacology. Drug treatments; Protozoal diseases; renal clearance; synergism; Trypanocidal Agents; Trypanocidal Agents - pharmacokinetics; Trypanocidal Agents - therapeutic use; Trypanosoma cruzi; Trypanosomiasis; Infection; Therapeutic drug monitoring; Protozoal disease; Chemotherapy; Treatment; HPLC chromatography; Preclinical trial; Chagas disease; Parasitosis; Method; Trypanosomiasis
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.05785-11

A combination of drugs in experimental chemotherapy of Chagas' disease may increase the effectiveness of treatment. To evaluate the possible mechanisms that influence the improvement of therapy, we investigated the pharmacokinetic interaction between benznidazole and itraconazole in a murine model treated orally with single doses of 5 mg of each compound separately or together. Blood samples from treated mice were collected at different intervals for 48 h, and a high-performance liquid chromatography (HPLC)-UV method was used to quantify both drugs in the plasma. A decrease of 1.5-fold in the maximum drug concentration in the plasma (Cmax) and an increase of 2.66-fold in the volume of distribution (V) and 7.5-fold in the elimination half-life (t1/2β) of benznidazole when coadministered with itraconazole were observed. The parameters area under the curve (AUC0-t), area under the curve extrapolated to infinity (AUC0-∞), time to maximum concentration of drug in serum (Tmax), and clearance (CL) for benznidazole were not significantly different in this therapeutic regime. None of the evaluated parameters for ITC demonstrated a significant difference between isolated and associated administration. These results suggest that the main effect of this interaction leads to accumulation of benznidazole in the biological system. This effect may contribute to the improved therapeutic efficacy of this combination of drugs, in addition to synergism of the different mechanisms of action of benznidazole and itraconazole against Trypanosoma cruzi in vivo.