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1.
Molecules ; 26(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802579

RESUMEN

Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodeficiency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g., H2BK47, H4K32), histidine (e.g., H2BH110, H4H76), and serine (e.g., H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83, and H4H76 were found to be potential hot spots for NVP incorporation. Notably, a remarkable selectivity to the imidazole ring of histidine was observed, with modification by NVP detected in three out of the 11 histidine residues of histones. This suggests that NVP-modified histidine residues of histones are prospective markers of the drug's bioactivation and/or toxicity. Importantly, NVP-derived modifications were identified at sites known to determine chromatin structure (e.g., H4H76) or that can undergo multiple types of post-translational modifications (e.g., H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.


Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Histonas/química , Histonas/metabolismo , Nevirapina/química , Nevirapina/metabolismo , Proteoma/análisis , Humanos , Estructura Molecular
2.
Int J Mol Sci ; 21(22)2020 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-33238468

RESUMEN

Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the bacteria to coexist in a state of asymptomatic latency. This last state can be sustained for years or even decades, waiting for a breach in the immune system to become active again. Furthermore, most current therapies are not efficacious against this state, failing to completely clear the infection. Over the years, a series of experimental methods have been developed to mimic the latent state, currently used in drug discovery, both in vitro and in vivo. Most of these methods focus in one specific latency inducing factor, with only a few taking into consideration the complexity of the granuloma and the genomic and proteomic consequences of each physiological factor. A series of targets specifically involved in latency have been studied over the years with promising scaffolds being discovered and explored. Taking in account that solving the latency problem is one of the keys to eradicate the disease, herein we compile current therapies and diagnosis techniques, methods to mimic latency and new targets and compounds in the pipeline of drug discovery.


Asunto(s)
Proteínas Bacterianas/genética , Tuberculosis Latente/tratamiento farmacológico , Mycobacterium tuberculosis/genética , Proteómica , Proteínas Bacterianas/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Sistema Inmunológico/efectos de los fármacos , Tuberculosis Latente/genética , Tuberculosis Latente/microbiología , Terapia Molecular Dirigida , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad
3.
Arch Toxicol ; 91(3): 1199-1211, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27417440

RESUMEN

The development of metabolically competent in vitro models is of utmost importance for predicting adverse drug reactions, thereby preventing attrition-related economical and clinical burdens. Using the antiretroviral drug nevirapine (NVP) as a model, this work aimed to validate rat hepatocyte 3D spheroid cultures as competent in vitro systems to assess drug metabolism and bioactivation. Hepatocyte spheroids were cultured for 12 days in a stirred tank system (3D cultures) and exposed to equimolar dosages of NVP and its two major Phase I metabolites, 12-OH-NVP and 2-OH-NVP. Phase I NVP metabolites were detected in the 3D cultures during the whole culture time in the same relative proportions reported in in vivo studies. Moreover, the modulation of SULT1A1 activity by NVP and 2-OH-NVP was observed for the first time, pointing their synergistic effect as a key factor in the formation of the toxic metabolite (12-sulfoxy-NVP). Covalent adducts formed by reactive NVP metabolites with N-acetyl-L-cysteine and bovine serum albumin were also detected by high-resolution mass spectrometry, providing new evidence on the relative role of the reactive NVP metabolites, 12-sulfoxy-NVP, and NVP quinone methide, in toxicity versus excretion pathways. In conclusion, these results demonstrate the validity of the 3D culture system to evaluate drug bioactivation, enabling the identification of potential biomarkers of bioactivation/toxicity, and providing new evidence to the mechanisms underlying NVP-induced toxic events. This model, integrated with the analytical strategies described herein, is of anticipated usefulness to the pharmaceutical industry, as an upstream methodology for flagging drug safety alerts in early stages of drug development.


Asunto(s)
Hepatocitos/efectos de los fármacos , Nevirapina/farmacocinética , Esferoides Celulares/efectos de los fármacos , Acetilcisteína/química , Acetilcisteína/metabolismo , Animales , Arilsulfotransferasa/metabolismo , Biotransformación , Técnicas de Cultivo de Célula/métodos , Hepatocitos/metabolismo , Inactivación Metabólica , Ratas , Reproducibilidad de los Resultados
4.
J Antimicrob Chemother ; 69(2): 476-82, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24051761

RESUMEN

OBJECTIVES: Nevirapine is widely used for the treatment of HIV-1 infection; however, its chronic use has been associated with severe liver and skin toxicity. Women are at increased risk for these toxic events, but the reasons for the sex-related differences are unclear. Disparities in the biotransformation of nevirapine and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in nevirapine biotransformation as a potential factor in nevirapine-induced toxicity. METHODS: All included subjects were adults who had been receiving 400 mg of nevirapine once daily for at least 1 month. Blood samples were collected and the levels of nevirapine and its phase I metabolites were quantified by HPLC. Anthropometric and clinical data, and nevirapine metabolite profiles, were assessed for sex-related differences. RESULTS: A total of 52 patients were included (63% were men). Body weight was lower in women (P = 0.028) and female sex was associated with higher alkaline phosphatase (P = 0.036) and lactate dehydrogenase (P = 0.037) levels. The plasma concentrations of nevirapine (P = 0.030) and the metabolite 3-hydroxy-nevirapine (P = 0.035), as well as the proportions of the metabolites 12-hydroxy-nevirapine (P = 0.037) and 3-hydroxy-nevirapine (P = 0.001), were higher in women, when adjusted for body weight. CONCLUSIONS: There was a sex-dependent variation in nevirapine biotransformation, particularly in the generation of the 12-hydroxy-nevirapine and 3-hydroxy-nevirapine metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex-dependent dimorphic profile of nevirapine toxicity.


Asunto(s)
Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/sangre , Nevirapina/efectos adversos , Nevirapina/sangre , Caracteres Sexuales , Adulto , Biotransformación/efectos de los fármacos , Biotransformación/fisiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad
5.
ChemMedChem ; 18(24): e202300410, 2023 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-37845182

RESUMEN

While N-acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N-acetyl moiety for a N-carbamoyl group led to analogues with sub- and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug-susceptible and drug-resistant M. tuberculosis isolates. The new N-carbamoyl azaaurones exhibited improved microsomal stability, compared to their N-acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10-8 , a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Antituberculosos/farmacología , Antituberculosos/química , Solubilidad , Pruebas de Sensibilidad Microbiana
6.
Org Biomol Chem ; 10(23): 4554-61, 2012 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-22569890

RESUMEN

We report the oxidation of the first line anti-HIV drug efavirenz (EFV), mediated by a bio-inspired nonheme Fe-complex. Depending upon the experimental conditions this system can be tuned either to yield the major EFV metabolite, 8-hydroxy-EFV, in enantiomerically pure form or to mimic cytochrome P450 (CYP) activity, yielding 8-hydroxy-EFV and 7-hydroxy-EFV, the two phenolic EFV metabolites reported to be formed in vivo. The successful oxidation of the anti-estrogen tamoxifen and the equine estrogen equilin into their CYP-mediated metabolites supports the general application of bio-inspired nonheme Fe-complexes in mirroring CYP activity.


Asunto(s)
Fármacos Anti-VIH/química , Benzoxazinas/química , Materiales Biomiméticos/química , Fenol/química , Xenobióticos/química , Alquinos , Animales , Ciclopropanos , Caballos , Estructura Molecular , Oxidación-Reducción , Fenol/metabolismo
7.
Molecules ; 17(3): 2616-27, 2012 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-22391597

RESUMEN

Nevirapine (NVP) is an anti-HIV drug associated with severe hepatotoxicity and skin rashes, which raises concerns about its chronic administration. There is increasing evidence that metabolic activation to reactive electrophiles capable of reacting with bionucleophiles is likely to be involved in the initiation of these toxic responses. Phase I NVP metabolism involves oxidation of the 4-methyl substituent and the formation of phenolic derivatives that are conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species prone to react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As part of a program aimed at evaluating the possible contribution of quinoid derivatives of Phase I phenolic NVP metabolites to the toxic responses elicited by the parent drug, we have investigated the oxidation of 2-hydroxy-NVP with dipotassium nitroso-disulfonate (Frémy's salt), mimicking the one-electron oxidation involved in enzyme-mediated metabolic oxidations. We report herein the isolation and full structural characterization of a 1H-pyrrole-2,5-dione derivative as a major product, stemming from an unusual pyridine ring contraction.


Asunto(s)
Nevirapina/análogos & derivados , Nevirapina/química , Fenoles/química , Cristalografía por Rayos X , Hidrólisis , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Químicos , Conformación Molecular , Estructura Molecular , Compuestos Nitrosos/química , Oxidantes/química , Oxidación-Reducción
8.
Toxicol Lett ; 260: 28-35, 2016 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-27543169

RESUMEN

Efavirenz is a drug of choice for adults and children infected with the human immunodeficiency virus. Notably, up to 35% of patients on efavirenz suffer from mood changes. This work aimed to investigate efavirenz biotransformation into 8-hydroxy-efavirenz as an up-stream event of mood changes and to evaluate the suitability of 8-hydroxy-efavirenz biomonitoring for the minimization of these manifestations. A case-control study with two age-matched groups of HIV-infected male patients was performed in a group without adverse central nervous system complaints (28 patients) and a group presenting mood changes (14 patients). The plasma concentration of non-conjugated 8-hydroxy-efavirenz was higher in patients with mood changes (p=0.020). An association between efavirenz and 8-hydroxy-efavirenz-glucuronide was found (Spearman r=0.414, p<0.010), only within therapeutic efavirenz concentrations. This correlation was not observed in patients with toxic (>4mg/L) plasma concentrations of the parent drug. We conclude that metabolism to 8-hydroxy-efavirenz is associated with efavirenz-related mood changes, which suggests that the concentration of this metabolite is a suitable parameter for therapeutic drug monitoring aimed at controlling these manifestations. Moreover, our data suggest that 8-hydroxy-efavirenz is able to cross the blood-brain barrier and that the peripheral detoxification of 8-hydroxy-efavirenz by glucuronidation may be inhibited by toxic efavirenz concentrations.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Benzoxazinas/metabolismo , Benzoxazinas/farmacocinética , Monitoreo de Drogas/métodos , Infecciones por VIH/metabolismo , Trastornos del Humor/inducido químicamente , Síndromes de Neurotoxicidad/etiología , Inhibidores de la Transcriptasa Inversa/farmacocinética , Adulto , Alquinos , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Ansiedad/inducido químicamente , Ansiedad/diagnóstico , Ansiedad/epidemiología , Benzoxazinas/efectos adversos , Benzoxazinas/sangre , Benzoxazinas/uso terapéutico , Biomarcadores Farmacológicos/sangre , Biotransformación , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Ciclopropanos , Quimioterapia Combinada/efectos adversos , Estudios de Factibilidad , Glucurónidos/sangre , Glucurónidos/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Humanos , Masculino , Fase II de la Desintoxicación Metabólica , Persona de Mediana Edad , Trastornos del Humor/diagnóstico , Trastornos del Humor/epidemiología , Síndromes de Neurotoxicidad/diagnóstico , Síndromes de Neurotoxicidad/epidemiología , Prevalencia , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéutico
9.
Eur J Med Chem ; 74: 7-11, 2014 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-24440376

RESUMEN

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor administered as first line treatment against HIV-1. The major drawbacks of EFV therapy are neurotoxicity and hepatotoxicity, which may result from bioactivation to reactive metabolites capable of reacting with bionucleophiles. We investigated the in vitro oxidation of the phenolic EFV metabolites, 7-hydroxy-efavirenz (7-OH-EFV) and 8-hydroxy-efavirenz (8-OH-EFV), with Frémy's salt. A quinoline derivative, 6-chloro-2-cyclopropyl-4-(trifluoromethyl)quinolin-7-ol, presumably stemming from a radical rearrangement, was selectively obtained from 7-OH-EFV in 10% yield. In contrast, when subjected to the same oxidation conditions, 8-OH-EFV was considerably more prone to oxidative degradation and yielded multiple products. Among these, a quinone-imine derivative was tentatively identified upon LC-ESI-MS/MS analysis of the reaction mixture. These observations demonstrate a remarkable difference in the reactivities of the two phenolic EFV metabolites under oxidative conditions. Moreover, taking into consideration the toxicological significance of quinone-imine derivatives, these findings may explain earlier reports that 8-OH-EFV is a more potent toxicant than 7-OH-EFV in model test systems.


Asunto(s)
Fármacos Anti-VIH/química , Fenoles/química , Inhibidores de la Transcriptasa Inversa/química , Cromatografía Liquida , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem
10.
Int J Antimicrob Agents ; 42(5): 443-6, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24051055

RESUMEN

The potential for co-prescription of the anti-human immunodeficiency virus (anti-HIV) drug efavirenz (EFV) and the oral anticoagulant warfarin (WAR) is currently high as EFV is a drug of choice for HIV type 1 infection and because cardiovascular disease is increasing among HIV-infected individuals. However, clinical reports of EFV-WAR interaction, leading to WAR overdosing, call for elucidation of the mechanisms involved in this drug-drug interaction. Here we present the first report demonstrating competition of the two drugs for the same binding site of human serum albumin. Using ligand-based nuclear magnetic resonance experiments, this study proves that EFV has an effect on the concentration of free WAR. This previously unidentified EFV-WAR interaction represents a potential risk factor that should be taken into account when considering treatment options.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Anticoagulantes/farmacocinética , Benzoxazinas/farmacocinética , Albúmina Sérica/metabolismo , Warfarina/farmacocinética , Alquinos , Unión Competitiva , Ciclopropanos , Interacciones Farmacológicas , Humanos , Espectroscopía de Resonancia Magnética , Albúmina Sérica Humana
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