**1. Introduction**

Statins are among the most widely prescribed drug classes in the world. They are used to lower low density lipoprotein-cholesterol (LDL-C) serum levels in patients for the prevention and treatment of cardiovascular diseases [1]. They exhibit a wide range of effects: additionally to the inhibition of cholesterol synthesis, they modulate inflammatory response, affect coagulation system, induce apoptosis and decrease oxidative stress [2].

If statins are not successful, guidelines recommend peroxisome proliferator-activated receptor alpha (PPARα) agonists (fibrates) for the managemen<sup>t</sup> of hypertriglyceridemia [3]. Studies have shown that fibrates also have pleiotropic effects like improving endothelial dysfunction [4,5], inhibiting the expression of adhesion molecules and inflammatory cytokines [6] and decreasing oxidative stress and nitric oxide production [5]. Moreover, fibrates can inhibit coagulation [4,7] and improve haemorheologic parameters [8].

However, these agents also have limitations, most importantly due to pharmacokinetic interactions, such as an increased risk of myopathy through a combination of statins and gemfibrozil [9], or side effects, which include digestive disorders, reversible elevation in serum creatinine and liver enzymes [10].

It is conceivable that some of the adverse events like liver dysfunction or gastrointestinal discomfort are caused by mitochondrial dysfunction [11,12]. However, data about effects of statins and fibrates on mitochondrial function in different organs are inconsistent and partially contradictory. Data about effects of these drugs on colonic mitochondria are lacking completely.

Statins can affect skeletal muscle mitochondria in vitro by inhibiting respiratory chain complexes and oxidative capacity [12,13], decreasing mitochondrial membrane potential [13], uncoupling oxidative phosphorylation, inducing mitochondrial swelling and apoptosis [13] and decreasing mitochondrial density [14]. Statins also uncouple state 2 respiration and can inhibit the activity of the complexes of the respiratory chain in liver mitochondria, but the effect is drug-dependent (simvastatin has a strong deteriorating effect, while pravastatin does not seem to affect hepatic mitochondria) [15].

Hydrophilic statins (e.g., pravastatin) are considered as less 'mitotoxic' compared to lipophilic statins such as cerivastatin, fluvastatin, atorvastatin and simvastatin [13]. Even if some authors failed to show any effects of pravastatin on mitochondrial respiration in muscle [13], in the liver [16] and in HL-1 cardiomyocytes [1], cases of drug induced hepatotoxicity are reported [17]. Furthermore, evidence exists for even positive effects of statins on mitochondrial function. Bouitbir et al. showed that statins promote mitochondrial function and mitochondrial biogenesis in human heart muscle [18].

Effects of fibrates on mitochondrial function are also not clearly understood. From one side, in vitro results sugges<sup>t</sup> impaired mitochondrial function, via direct inhibition of mitochondrial respiration (mainly complex I) [19], by membrane depolarization [20] and through increases in uncoupled respiration [15,21]. From the other side, fibrates as PPAR-α agonists can enhance mitogenesis and therefore mitochondrial activity [22]. There are also differences among single fibrates concerning effects on mitochondrial function and gemfibrozil seems to be less mitotoxic than the other drugs from this group [19].

Taken together, the effects of statins and fibrates on mitochondrial function in different organs have been insufficiently examined. Data concerning hepatic mitochondria are inconsistent and about other organs like colon are lacking completely. The aim of this study was therefore to investigate the concentration dependent effect of pravastatin (statin) and gemfibrozil (fibrate) on hepatic and colonic mitochondrial respiration in tissue homogenates from healthy rats.

#### **2. Materials and Methods**
