Combined effect of telmisartan and fluvastatin on arachidonic acid metabolism in human liver microsomes

Abstract

1. Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA) via cytochrome P450s, have a protective effect on the cardiovascular system involving vasodilation. We have previously demonstrated that telmisartan (TEL) inhibits EETs production from AA in vitro.

2. The objectives of the study were to examine the inhibitory effect of fluvastatin (FLU), an inhibitor of CYP2C9, and the combined effect of TEL and FLU on the production of EETs using human liver microsomes. The combined effect of TEL and FLU was evaluated using two methods, the fixed concentration method and the fixed ratio method.

3. FLU significantly reduced total eicosanoids (sum of EETs and their subsequent metabolites dihydroxyeicosatrienoic acids) production at > 0.25 µM. The results of the fixed concentration method indicated that the addition of the other inhibitor resulted in significant reduction of the production of total eicosanoids in a concentration-dependent manner. In the fixed ratio method, the combination of TEL and FLU over all concentration ratios tested did not produce a horizontal shift in the dose response curves.

4. Our results showing an additive combined effect of TEL and FLU on AA metabolism, suggest that concomitant treatment with TEL and FLU would theoretically affect the vascular tone mediated by EETs from AA.

Keywords:

• Combined effect
• dihydroxyeicosatrienoic acid
• epoxyeicosatrienoic acid
• fluvastatin
• telmisartan