RESUMEN
AIM: To develop LC-MS /MS method for simultaneous determination of simvastatin and simvastatin acid concentrations in rat plasma, and investigate the pharmacokinetic effects of Wuzhi capsule (WZC) on simvastatin and simvastatin acid concentrations in rats. METHODS: The method was based on simple liquid liquid extraction (LLE) with lovastatin as internal standard. Agilent Eclipse-C
RESUMEN
Cardiovascular disease (CVD) is the most common cause of death in patients with non-alcoholic fatty liver disease (NAFLD). New therapeutic strategies which have the potential for slowing down the evolution of NAFLD and reducing CVD-related mortality are urgently needed. Statins are well recognized in the treatment of dyslipidemia, but their use in the treatment of NAFLD is limited due to the safety concerns. Ilexgenin A (IA) is one of the main bioactive compounds in 'Shan-lv-cha', an herbal tea commonly used in China. In the present study, we investigated the possible synergistic therapeutic effects of IA and simvastatin (SV) on NAFLD. IA or SV showed beneficial effects on the rats with NAFLD by lowering the liver weight, liver index and plasma levels of alanine aminotransferase and aspartate aminotransferase, regulating abnormal metabolism of lipids and ameliorating steatosis in liver. IA significantly enhanced the hypolipidemic and anti-inflammation effects of SV. Furthermore, a sensitive, accurate, convenient and reproducible LC-MS method was developed to investigate the effects of IA on the pharmacokinetics of SV. No significant changes were observed in pharmacokinetic parameters of SV and simvastatin hydroxy acid in the IA plus SV co-treated group in comparison with those in the group treated with SV alone. The mRNA levels and activity of CYP3A1 were not altered by IA. In conclusion, the results obtained from the present study should be helpful for further clinical application of SV and IA alone or in combination.
Asunto(s)
Animales , Masculino , Ratas , Alanina Transaminasa , Metabolismo , Aspartato Aminotransferasas , Metabolismo , Citocromo P-450 CYP3A , Genética , Metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Lípidos , Sangre , Hígado , Metabolismo , Patología , Estructura Molecular , Enfermedad del Hígado Graso no Alcohólico , Sangre , Quimioterapia , Ratas Sprague-Dawley , Simvastatina , Farmacocinética , Usos Terapéuticos , Transcripción Genética , Triterpenos , Química , Usos TerapéuticosRESUMEN
Cardiovascular disease (CVD) is the most common cause of death in patients with non-alcoholic fatty liver disease (NAFLD). New therapeutic strategies which have the potential for slowing down the evolution of NAFLD and reducing CVD-related mortality are urgently needed. Statins are well recognized in the treatment of dyslipidemia, but their use in the treatment of NAFLD is limited due to the safety concerns. Ilexgenin A (IA) is one of the main bioactive compounds in 'Shan-lv-cha', an herbal tea commonly used in China. In the present study, we investigated the possible synergistic therapeutic effects of IA and simvastatin (SV) on NAFLD. IA or SV showed beneficial effects on the rats with NAFLD by lowering the liver weight, liver index and plasma levels of alanine aminotransferase and aspartate aminotransferase, regulating abnormal metabolism of lipids and ameliorating steatosis in liver. IA significantly enhanced the hypolipidemic and anti-inflammation effects of SV. Furthermore, a sensitive, accurate, convenient and reproducible LC-MS method was developed to investigate the effects of IA on the pharmacokinetics of SV. No significant changes were observed in pharmacokinetic parameters of SV and simvastatin hydroxy acid in the IA plus SV co-treated group in comparison with those in the group treated with SV alone. The mRNA levels and activity of CYP3A1 were not altered by IA. In conclusion, the results obtained from the present study should be helpful for further clinical application of SV and IA alone or in combination.
Asunto(s)
Animales , Masculino , Ratas , Alanina Transaminasa , Metabolismo , Aspartato Aminotransferasas , Metabolismo , Citocromo P-450 CYP3A , Genética , Metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Lípidos , Sangre , Hígado , Metabolismo , Patología , Estructura Molecular , Enfermedad del Hígado Graso no Alcohólico , Sangre , Quimioterapia , Ratas Sprague-Dawley , Simvastatina , Farmacocinética , Usos Terapéuticos , Transcripción Genética , Triterpenos , Química , Usos TerapéuticosRESUMEN
Simvastatin is a lipid-lowering drug that is metabolized to its active metabolite simvastatin acid (SA). We developed and validated a sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to quantitate SA in human plasma using a liquid-liquid extraction method with methanol. The protonated analytes generated in negative ion mode were monitored by multiple reaction monitoring. Using 500-mL plasma aliquots, SA was quantified in the range of 0.1-100 ng/mL. Calibration was performed by internal standardization with lovastatin acid, and regression curves were generated using a weighting factor of 1/χ2. The linearity, precision, and accuracy of this assay for each compound were validated using quality control samples consisting of mixtures of SA (0.1, 0.5, 5, and 50 ng/mL) and plasma. The intra-batch accuracy was 95.3-107.8%, precision was -2.2% to -3.7%, and linearity (r2) was over 0.998 in the standard calibration range. The chromatographic running time was 3.0 min. This method sensitively and reliably measured SA concentrations in human plasma and was successfully used in clinical pharmacokinetic studies of simvastatin in healthy Korean adult male volunteers.