Major benznidazole metabolites in patients treated for Chagas disease: Mass spectrometry-based identification, structural analysis and detoxification pathways

Carlos, Pérez Montilla; Moroni, Samanta; Moscatelli, Guillermo; Rocco, Daniela Marisa; González, Nicolás; Altcheh, Jaime; Bournissen, Facundo García

doi:10.1016/j.toxlet.2023.02.001

Cited by 3 publications

(2 citation statements)

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“…Our group has identified potential BNZ metabolites in humans [ 33 , 35 ], but more work remains to be done in this area. We have recently characterized over 15 BNZ metabolites in pediatric patients’ urine using a combination of targeted and non-targeted LC-MS/MS approach[ 36 ], including BNZ phase 1 (e.g. reduction and oxidation products) and phase 2 (e.g.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation

et al. 2023

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Background There is a major need for information on pharmacokinetics (PK) of benznidazole (BNZ) in children with Chagas disease (CD). We conducted a multicentre population PK, safety and efficacy study in children, infants and neonates with CD treated with BNZ (formulated in 100 mg tablets or 12.5 mg dispersible tablets, developed by the pharmaceutical company LAFEPE, in a collaboration with DNDi). Methods 81 children 0–12 years old were enrolled at 5 pediatric centers in Argentina. Diagnosis of T. cruzi infection was confirmed by direct microscopic examination, or at least two positive conventional serological tests. Subject enrolment was stratified by age: newborns to 2 years (minimum of 10 newborns) and >2–12 years. BNZ 7.5 mg/kg/d was administered in two daily doses for 60 days. Five blood samples per child were obtained at random times within pre-defined time windows at Day 0 at 2–5 h post-dose; during steady state, one sample at Day 7 and at Day 30; and two samples at 12–24 h after final BNZ dose at Day 60. The primary efficacy endpoint was parasitological clearance by qualitative PCR at the end of treatment. Results Forty-one (51%) patients were under 2 years of age (including 14 newborns <1 month of age). Median age at enrolment was 22 months (mean: 43.2; interquartile range (IQR) 7–72 months). The median measured BNZ Cmax was 8.32 mg/L (IQR 5.95–11.8; range 1.79–19.38). Median observed BNZ Cmin (trough) concentration was 2 mg/L (IQR 1.25–3.77; range 0.14–7.08). Overall median simulated Css was 6.3 mg/L (IQR 4.7–8.5 mg/L). CL/F increased quickly during the first month of postnatal life and reached adult levels after approximately 10 years of age. Negative qPCR was observed at the end of treatment in all 76 patients who completed the treatment. Five patients discontinued treatment (3 due to AEs and 2 due to lack of compliance). Conclusion We observed lower BNZ plasma concentrations in infants and children than those previously reported in adults treated with comparable mg/kg doses. Despite these lower concentrations, pediatric treatment was well tolerated and universally effective, with a high response rate and infrequent, mild AEs. Trial registration Registered in clinicaltrials.gov #NCT01549236.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation

et al. 2023

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“…Consequently, distinguishing them from the metabolites in vivo becomes challenging [ [12] , [13] , [14] ], thereby significantly impacting the accuracy of medicinal material metabolism results [ 15 ], and leading to an unclear understanding of the pharmacodynamic material basis in vivo [ 16 , 17 ]. Traditional studies on the in vivo metabolism of medicinal have typically relied on analyzing the metabolic pathways of representative components and predicting metabolites for similar components to evaluate the efficacy of traditional Chinese medicine metabolism, or comparing chemical fingerprints of plant materials with metabolite profiles to identify in vivo metabolites [ [18] , [19] , [20] ]. However, these traditional methods involve complex data processing, large sample size, and procedures.…”

Section: Introductionmentioning

confidence: 99%

The mysteries of pharmacokinetics and in vivo metabolism of Oroxylum indicum (L.) Kurz: A new perspective from MSOP method

Zhang,

Wang

et al. 2024

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Identification and Quantitative Analysis of the Pharmacologically Active Components of Jianxin Granules by UHPLC-QTOF-MS/MS-Based Metabolomics

Zhang,

Chen,

Guo

et al. 2024

j biobased mat bioenergy

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Jianxin Granules, a Traditional Chinese Medicine (TCM), consisting of eight flavors, including Huang Qi (astragalus), Hong Shen (red ginseng), Pu Huang (pollen typhae), Dan Shen (salvia miltiorrhiza), Zhu Ling (polyporus), Bai Zhu (atractylodes macrocephala), Gui Zhi (cassia twig), Ting Li Zi (semen lepidii). Jianxin granules has a multi-system, multi-target, and multi-directional comprehensive regulatory effect on inhibiting ventricular remodeling, which is an effective formulation for the prevention and treatment of heart failure, and has a good application prospect. However, many of the ingredients, including pharmacologically active ingredients, in the Jianxin granules remain unclear. Here, we attempted to develop a metabolomics method of component identification, quantitation, pattern recognition, and cross-comparison of Jianxin granules. Chemical analysis, component identification and quantification analyse of Jianxin granules were conducted with a combination of UHPLC-QTOF-MS/MS with bioinformatics. Assessment of the correlation between technical and bio-replicated pharmacological active ingredients was implemented by Principal Component Analysis (PCA), in addition to Partial Least Squares Discriminant Analysis (PLS-DA). UHPLC-QTOFMS/ MS, a metabolomics method, was developed and adapted to characterize Jianxin granules, which consisted of 178 to 216 molecular signatures. The quantitative analysis of 95 frequently occurring molecular signatures of Jianxin granules was carried out by a single exogenous reference internal standard. Of these, 47 have been identified using diverse databases, including 2 glycosylglycerol derivatives, 2 lipids, 2 spiro compounds, 2 cyclohexanecarboxylic acids, 2 glycosides, 5 terpenoids, 7 oligopeptides, 17 favonoids, and 8 various compounds, such as hydroxycoumarin, chalcone, benzofuran, benzodioxole, benzaldehyde, aromatic ketone, and alkyl cafeate ester. The established method demonstrates robust reliability and reproducibility, making it suitable for various applications including compositional identification, quantification, and quality assessment of the pharmacologically active constituents in Jianxin granules.

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Major benznidazole metabolites in patients treated for Chagas disease: Mass spectrometry-based identification, structural analysis and detoxification pathways

Cited by 3 publications

References 77 publications

Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation

Population pharmacokinetics of benznidazole in neonates, infants and children using a new pediatric formulation

The mysteries of pharmacokinetics and in vivo metabolism of Oroxylum indicum (L.) Kurz: A new perspective from MSOP method

Identification and Quantitative Analysis of the Pharmacologically Active Components of Jianxin Granules by UHPLC-QTOF-MS/MS-Based Metabolomics

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