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New insights on nevirapine use: a mechanistic perspective of its toxic events
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Introdução: A nevirapina (NVP) é um fármaco amplamente utilizado para o tratamento da infecção pelo vírus da imunodeficiência humana de tipo 1 (VIH-1), no entanto, a sua utilização na terapêutica crónica tem sido associada à toxicidade hepática e cutânea. O sexo feminino é um factor de risco para o desenvolvimento destes eventos tóxicos, mas as razões para essa diferença entre o sexo feminino e masculino não estão completamente esclarecidas. Diferenças na biotransformação da NVP e na formação de metabolitos tóxicos podem ser as causas subjacentes. O presente trabalho teve como objectivo explorar as diferenças entre homens e mulheres na biotransformação da NVP, como um potencial factor de toxicidade induzida por este fármaco anti-retroviral.
Materiais e Métodos: Todos os indivíduos incluídos no presente estudo eram adultos com infecção por VIH-1 confirmada, tratados com 400 mg de NVP uma vez ao dia, durante pelo menos 1 mês. Foram colhidas amostras de sangue e os níveis de NVP e dos metabolitos de fase I foram determinados por cromatografia líquida de alta performance. Os dados antropométricos e clínicos e os perfis de metabolitos foram avaliados de forma a averiguar possíveis diferenças relacionadas com o sexo dos indivíduos.
Resultados: Foram incluídos 52 doentes (63% do sexo masculino). O peso corporal foi inferior nas mulheres (p = 0.028) e o sexo feminino foi associado a maiores níveis de fosfatase alcalina (p = 0.036) e lactato desidrogenase (p = 0.037). Os níveis plasmáticos de NVP (p = 0.030) e 3-hidroxi-NVP (p = 0.035), assim como as proporções de 12-hidroxi-NVP (p = 0.037) e 3-hidroxi-NVP (p = 0.001) foram maiores nas mulheres, quando ajustados pelo peso corporal dos indivíduos.
Discussão: Existem diferenças na biotransformação da NVP entre homens e mulheres, particularmente na formação de 12-hidroxi-NVP e 3-hidroxi-NVP. Estes resultados apontam para uma formação de metabolitos reactivos, que é dependente do sexo e que pode contribuir para o perfil de dimorfismo sexual associado às reacções tóxicas induzidas pela NVP.
Introduction: Nevirapine (NVP) is widely used for the treatment of human immunodeficiency virus type 1 (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 NVP and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in NVP biotransformation as a potential factor in NVP-induced toxicity. Materials and Methods: All included subjects were HIV-1-infected adults who had been receiving 400 mg of NVP once daily for at least 1 month. Blood samples were collected and the levels of NVP and its phase I metabolites were quantified by high-performance liquid chromatography. Anthropometric and clinical data, and NVP 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 NVP (p = 0.030) and the metabolite 3-hydroxy-NVP (p = 0.035), as well as the proportions of the metabolites 12-hydroxy-NVP (p = 0.037) and 3-hydroxy-NVP (p = 0.001), were higher in women, when adjusted for body weight. Conclusions: There was a sex-dependent variation in NVP biotransformation, particularly in the generation of the 12-hydroxy-NVP and 3-hydroxy-NVP metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex-dependent dimorphic profile of NVP toxicity.
Introduction: Nevirapine (NVP) is widely used for the treatment of human immunodeficiency virus type 1 (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 NVP and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in NVP biotransformation as a potential factor in NVP-induced toxicity. Materials and Methods: All included subjects were HIV-1-infected adults who had been receiving 400 mg of NVP once daily for at least 1 month. Blood samples were collected and the levels of NVP and its phase I metabolites were quantified by high-performance liquid chromatography. Anthropometric and clinical data, and NVP 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 NVP (p = 0.030) and the metabolite 3-hydroxy-NVP (p = 0.035), as well as the proportions of the metabolites 12-hydroxy-NVP (p = 0.037) and 3-hydroxy-NVP (p = 0.001), were higher in women, when adjusted for body weight. Conclusions: There was a sex-dependent variation in NVP biotransformation, particularly in the generation of the 12-hydroxy-NVP and 3-hydroxy-NVP metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex-dependent dimorphic profile of NVP toxicity.
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Microbiologia médica Biologia molecular Medicina tropical
Contexto Educativo
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Instituto de Higiene e Medicina Tropical