Comparison of simvastatin and simvastatin hydroxy acid complexation whit human serum albumin

Simvastatin (a HMG-COA reductase) is widely consumed drug in hyperlipidemia. Simvastatin is a lactone pro-drug which converts immediately to its acidic and active form (simvastatin hydroxyl acid) in body. Due to important role of human serum albumin (HSA) with drugs and their metabolites, molecular mechanism of such interactions should be studied to provide needed information for drug development and clinical purposes. The interaction between simvastatin and its active metabolite (simvastatin hydroxyl acid) with HSA has investigated in the current study. [1-2]Stock solutions of HSA in pH 7.4 were prepared daily and diluted using the suitable buffer to prepare working standards. The complex between the studied drugs and HSA was produced by the addition of suitable concentrations of the drugs to the HSA solution and the data were acquired after suitable incubation time. The 1:1 interaction was confirmed with the spectroscopic analysis for both compounds. Ksv=6.6×103 and intercept of 0.98 for simvastatin increased significantly to the order of 105 for its metabolite. The FTIR study revealed second structure variation of HSA due to complex formation both for simvastatin and its metabolite. The results showed that the metabolite of simvastatin is able to produce more stable complex with HSA (significant enhancement of αhelix%) in comparison with pro-drug. Simvastatin possessed lower interaction in comparison with its metabolite with HSA. This finding is consistent with this fact that the acidic compounds have higher binding constants. Significant lower binding of the simvastatin in comparison with its metabolite is a determinant factor in clinical modification of its dose and the related drug development studies. Similar approaches could be investigated in other pro-drugs, and the results would help researchers of the field.