ilexgenin-a and Non-alcoholic-Fatty-Liver-Disease

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.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cytochrome P-450 CYP3A; Diet, High-Fat; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Lipids; Liver; Male; Molecular Structure; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Simvastatin; Transcription, Genetic; Triterpenes

Ilex hainanensis Merr. is commonly used as a folk remedy for treating hypertension, dyslipidemia and inflammation in Traditional Chinese Medicine (TCMs) and it also has great potential to treat non-alcoholic fatty liver disease (NAFLD). Chlorogenic acid, kaempferol-7-O-β-d-glucoside, and ilexgenin A are three major bioactive components in I. hainanensis extract. In this study, a rapid, sensitive and convenient LC-MS method was developed for their simultaneous determination in the plasma of normal and NAFLD rats. The method was validated in terms of selectivity, linearity and sensitivity, and shows advantages in monitoring the pharmacokinetic behaviors of these three compounds. Results revealed the pharmacokinetic behaviors of chlorogenic acid, kaempferol-7-O-β-d-glucoside, and ilexgenin A could be significantly changed in NAFLD rats after oral administration of I. hainanensis extract compared with normal rats. The areas under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of the three analytes were greatly decreased and the plasma clearance (CL) for kaempferol-7-O-β-d-glucoside, Ilexgenin A were greatly increased in NAFLD rats. Meanwhile, the mean residence time (MRT) of kaempferol-7-O-β-d-glucoside and Ilexgenin A were increased in the NAFLD rats. This is the first report on the determination of the major bioactive components in rat plasma after oral administration of I. hainanensis extract. These results provided a meaningful basis for evaluating the clinical application of this medicine.

Topics: Administration, Oral; Animals; Biological Factors; Chlorogenic Acid; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Fatty Liver; Glycosides; Ilex; Kaempferols; Male; Medicine, Chinese Traditional; Non-alcoholic Fatty Liver Disease; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization; Triterpenes