GOPALA REDDY, A(MAJOR)SRINIVASA RAO, GANAND KUMAR, ARAJASEKHAR REDDY, ADILIP REDDY, GUNTURU2018-10-262018-10-262009-03http://krishikosh.egranth.ac.in/handle/1/5810082249THESESABSTRACT : A total of 56 male Sprague dawley rats of uniform weight and age were randomly divided into seven groups consisting of eight rats in each group after an acclimatization period of 3 weeks to evaluate the interaction of atorvastatin with garlic in induced dyslipidaemia. Group 1 served as plain control, while groups 2 and 3 were fed with high fat and high cholesterol diet throughout the experimental period. Groups 4,5,6 and 7 received 1% (100% dose), 0.5% (50% dose), 0.25% (25% dose) and 0.75% (75% dose) fresh garlic w/w in feed, respectively in addition to the high fat and high cholesterol diet and administered with 10 (100% dose), 5 (100% dose), 7.5 (100% dose) and 2.5 (25% dose) mg/kg atorvastatin respectively, while group 3 served as atorvastatin control, which received 10 mg/kg atorvastatin per day orally for 12 weeks. Blood collection was carried out at every two weeks interval for plasma biochemical analysis of total cholesterol, HDL cholesterol, triglycerides and creatinine and aspartate transaminase (AST). Single dose and multiple dose pharmacokinetic studies were performed at the beginning of the first dose and at the end of last dose of atorvastatin, respectively in groups 3 to 7. At the end of the experiment, liver and kidneys were collected for assay of TBARS, glutathione and SOD. Histological, histochemistry and electron microscopy studies were conducted on different organs at the end. All the treatment groups exhibited significant improvement in dyslipidaemic condition when compared with group 2 from 2nd week of treatment by reducing the TC, TG and LDL-C levels with subsequent increase in HDL-C levels. Group 4 was highly effective in correcting dyslipidaemia due to the synergistic pharmacodynamic actions of herb and drug. Plasma atorvastatin concentrations during multiple dose PK studies were significantly higher than single dose counterparts. PK parameters showed a significant increase in the garlic treated groups with high values of Cmax, AUC, AUMC, MRT and half-life which could be attributed to the inhibitory activity of garlic on drug transporters and metabolizing enzymes. High concentration of the drug in plasma in group 4, 5 and 3 resulted in toxicological manifestations in liver and kidney, which was evident from the increased plasma creatinine concentration, AST activity and oxidative stress. Histopathological studies on liver, kidney revealed moderate to severe damage in groups 4 and 5, which also exhibited mitochondrial damage on transmission electron microscopy. From this study, it can be concluded that garlic and atorvastatin exhibited positive pharmacodynamic interaction in reducing dyslipidaemias. The pharmacokinetic studies revealed that garlic increased the pharmacokinetic parameters and the toxicological studies indicated that high dose of atorvastatin + garlic has negative safety profile. Further studies are warranted to address the pharmacokinetic interactions of statin and garlic in detail.ennullThesis