Assuntos
Androstenos/efeitos adversos , Dissecção Aórtica/etiologia , Família 17 do Citocromo P450/antagonistas & inibidores , Hipertensão/complicações , Neoplasias da Próstata/terapia , Idoso , Dissecção Aórtica/diagnóstico , Aorta/diagnóstico por imagem , Aorta/efeitos dos fármacos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Angiografia por Tomografia Computadorizada , Di-Hidropiridinas/uso terapêutico , Ecocardiografia , Eletrocardiografia , Humanos , Hipertensão/tratamento farmacológico , MasculinoRESUMO
The aim of this study was to determine the steroidogenic endocrine disrupting effect of three widely used serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol, using two in vitro models, the H295R assay and a recombinant CYP17 enzyme assay. Steroid hormones were quantified using LC-MS/MS. Duloxetine showed endocrine disrupting effects at 5-20µM with CYP17 being the main target. Venlafaxine also affected the steroidogenesis, mainly by affecting the CYP17 lyase reaction, although at much higher concentrations i.e. 100µM. Tramadol only exerted minor effects on the steroidogenesis with the lowest observed effect at 314µM. Based on the H295R results, the inhibition of CYP17 by duloxetine and venlafaxine was investigated in a recombinant CYP17 assay with the use of the 4 major CYP17 substrates pregnenolone, progesterone, 17α-hydroxypregnenolone and 17α-hydroxyprogesterone. Both duloxetine and venlafaxine inhibited CYP17 enzyme activity, but duloxetine was most potent. IC50-values were in the range 5.3-21µM for duloxetine and 1318-2750µM for venlafaxine. Overall, results from the recombinant CYP17 assay confirmed the results from the H295R cell assay. Using testosterone as end point, the margin of safety (defined as NOAEL/Cmax) for duloxetine was 1.6 indicating that duloxetine may have endocrine disrupting effects. In contrast, venlafaxine and tramadol showed higher margins of safety (venlafaxine: 24; tramadol: 157) indicating a lower potential to disrupt the human steroidogenesis.
Assuntos
Córtex Suprarrenal/efeitos dos fármacos , Família 17 do Citocromo P450/antagonistas & inibidores , Cloridrato de Duloxetina/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Tramadol/efeitos adversos , Cloridrato de Venlafaxina/efeitos adversos , Córtex Suprarrenal/metabolismo , Corticosteroides/biossíntese , Corticosteroides/química , Corticosteroides/metabolismo , Analgésicos Opioides/efeitos adversos , Antidepressivos/efeitos adversos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450/efeitos adversos , Família 17 do Citocromo P450/genética , Família 17 do Citocromo P450/metabolismo , Humanos , Limite de Detecção , Estrutura Molecular , Nível de Efeito Adverso não Observado , Concentração Osmolar , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Reprodutibilidade dos TestesRESUMO
Abiraterone is an inhibitor of androgen biosynthesis indicated for the treatment of metastatic castration-resistant prostate cancer. Common side effects include diarrhea, edema, hypokalemia, hypertension, and liver function test abnormalities. We report a case of rhabdomyolysis developing in association with the use of abiraterone. Following discontinuation of abiraterone, creatine kinase concentrations decreased gradually throughout the duration of the hospitalization.
