Chagas disease is a serious public health problem in Latin America and, due to migration, in other non-endemic regions. Benznidazole (BNZ) is first choice drug in pediatric therapeutics. However, little is known regarding its metabolism in humans. The aim of the study was to isolate and identify products of human BZN metabolism in urine samples obtained from a pediatric Chagas patient and a healthy adult volunteer both treated with BZN. Urine samples were collected after dose of BNZ. Urine was treated with β-glucuronidase followed by an extraction procedure under two different pH conditions and a HPLC/UV and MS/MS identification of BZN and its metabolites. BZN (m/z 260.09847) was identified in all urine extracts. Peaks from each extracted chromatograms were selected for MS and MS/MS identification. Three compounds structurally related to BZN were identified: BZN-Na+ (m/z 283.08009), N-amine-BZN (m/z 230.12307) and N-hydroxi-amine-BZN (m/z 246.11702). BNZ-Na+ was identified in all extracts, but N-amine-BZN and N-hydroxi-amine-BZN were only observed in those extracts treated with β-glucuronidase. This is the first experimental report showing elimination of BZN N-reduced metabolites in urine. As they were released after treatment with β-glucuronidase it can be suggested that glucuronization plays a role in BNZ metabolism and renal elimination.

A doença de Chagas afeta aproximadamente 10 milhões de pessoas na América do Sul e 1,5 milhão na Argentina. A transmissão congênita é a mais importante em áreas urbanas. Existem dois medicamentos aprovados para o tratamento: nifurtimox (Laboratórios Bayer) e benznidazol (BNZ) (Laboratórios Roche, LAFEPE e Elea), desenvolvidas há mais de 40 anos, e sua farmacologia e seu metabolismo em humanos têm sido pouco estudados. A informação disponível é praticamente inexistente em crianças e mulheres grávidas. O objetivo é fornecer estudos sistemáticos para uma farmacoterapêutica racional em crianças visto que foram comprovadas empiricamente como sendo altamente eficazes. Métodos bioanalíticos aplicáveis a matrizes biológicas como plasma, urina e leite materno para fármacos-mãe e para a identificação de metabólitos em amostras de pacientes em tratamento terapêutico foram desenvolvidos. A farmacocinética da população pediátrica aqui descrita para BNZ é conclusiva em relação às suas diferenças com a farmacocinética de adultos. Três compostos apresentados como metabólitos do BNZ foram identificados. A transferência do referido medicamento para o leite materno não representa risco para o lactente. Essas evidências oferecem informações para melhorar os protocolos de tratamento existentes, buscando uma farmacoterapia adaptada à idade e um uso mais seguro dos medicamentos em crianças e eventualmente em adultos.

Chagas disease affects approximately 10 million people in South America and 1.5 million in Argentina. Congenital transmission is most important in urban areas. There are two drugs approved for treatment: nifurtimox (Bayer) and benznidazole (BNZ) (Roche, LAFEPE, Elea),developed more than 40 years ago. Their pharmacology and metabolism in humans have been seldom studied. The information available on children and pregnant women is virtually non-existent. The aim of this study is to provide systematic studies towards a rational pharmacotherapeutic sin children, which has been empirically proven to be highly effective. Bioanalytical methods were developed for plasma, urine and breast milk for parent drugs and for the identification of their metabolites in samples of patients under treatment. The pediatric population pharmacokinetics described here for BNZ is conclusive about their differences from adult pharmacokinetics. Three compounds presented as BNZ metabolites were identified. The transfer of this drug to the breast milk does not present a risk to the infant. These evidences offer information to improve the existing treatment protocols, seeking a pharmacotherapy adapted to the age and a safer use of the drugs in children and eventually in adults.

La enfermedad de Chagas afecta aproximadamente a 10 millones de personas en Sudamérica y 1,5 millones en la Argentina. La transmisión congénita es la más importante en áreas urbanas. Existen dos drogas aprobadas para el tratamiento: nifurtimox (Laboratorios Bayer) y benznidazol (BNZ) (Laboratorios Roche, LAFEPE y Elea) que fueron desarrolladas hace más de 40 años y cuya farmacología y metabolismo en humanos han sido poco estudiados. La información disponible es virtualmente inexistente en niños y mujeres embarazadas. Se busca aportar estudios sistemáticos hacia una farmacoterapéutica racional en niños ya que empíricamente ha demostrado gran efectividad. Se desarrollaron métodos bioanalíticos aplicables a matrices biológicas como plasma, orina y leche materna para las drogas madres y la identificación de metabolitos en muestras de pacientes bajo terapéutica. La farmacocinética poblacional pediátrica descripta aquí para BNZ es concluyente respecto de sus diferencias con la farmacocinética en adultos. Se identificaron tres compuestos presentados como metabolitos del BNZ. La transferencia de dicho fármaco a la leche materna no supone riesgo para el lactante. Estos resultados brindan información para mejorar los protocolos de tratamiento existentes buscando una farmacoterapéutica adaptada a la edad y un uso más seguro de los fármacos en niños y eventualmente en adultos.

Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruziquantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.