## 2 Bioavailability of Rosmarinic Acid and Its Metabolic Changes in the Human Body  
RA is partially metabolized to the coumaric acid and caffeic acid in the body of the rat [5], and the hypolipidemic effect of RA may also be a consequence of the action of its metabolites. For example, caffeic acid inhibited the synthesis of hepatic fatty acid synthase, 3-hydroxy-3-methylglutaryl CoA reductase and acyl-CoA:cholesterol acyltransferase activities and increased fatty acid \(\beta\)-oxidation activity in high-fat diet-induced obese mice [6]. Caffeic acid and sinapic acid increased serum estradiol concentrations in rats with estrogen deficiency, which may have contributed to the observed metabolic effects [7]. In the rat ovary ovulation, external ovarian tissues such as fatty tissue, skin, bones and brain are the source of estradiol. In these sites, C19 cannot be synthetized. Steroids C19 (androgens) can be converted to estrogens by aromatase. Therefore, it seems possible that RA or its metabolites increase the activity of aromatase. Caffeic acid increased estradiol and reduced total cholesterol concentrations only in rats that were fed standard food containing soy, and these effects were not observed in rats fed without soy with reduced phenolic acid contents [8]. It is therefore possible that at least some of the RA effects reported depend on the diet. RA showed similar beneficial effects on some lipid parameters and insulin resistance (HOMA-IR) as that demonstrated for sinapic acid in a parallel study [7]. Moreover, RA had positive effects on expression of hepatic genes or proteins involved in signaling insulin and glucose and lipid metabolism, such as insulin receptor substrate-1 (IRS-1), 5\({}^{\prime}\) AMP-activated protein kinase (AMPK), phosphoenolpyruvate carboxylase (PEPCK), glucose transporter 2 (GLUT2), forkhead box protein O1 (FOXO1), sterol regulatory element-binding protein 1 (SREBP1), and carnitine palmitosyltransferase 1 (CPT1) in diabetic rats [9]. The possible mechanism of action of RA on glucose and lipid metabolism may be mediated by peroxisome proliferatorator-activated receptor (PPAR) peroxidation; RA has been shown to activate these receptors. It should be noted that the lower RA dose (10 mg/kg) was sufficient to reduce the HOMA-IR index and the concentration of fructosamine, while a higher dose (50 mg/kg) was required to reduce the total cholesterol and  
Figure 1: Chemical structure of rosmarinic acid. triglyceride levels in rats with estrogen deficiency. Moreover, RA and its metabolites can directly neutralize reactive oxygen species (ROS) [10] and thereby reduce the formation of oxidative damage products. The antioxidant activity of RA directly derives from its structure, namely the presence of 4 hydrogens in the phenolic system and two catecholic moieties, which give this compound polar character. Electrochemical studies have shown that RA oxidizes in two steps. In the first step, the rest of the caffeic acid is oxidized and in the second step the residue of 3,4-dihydroxypropyl lactic acid. RA is therefore considered to be the strongest antioxidant of all hydroxycinnamic acid derivatives [11]. Inhibition of the production of advanced glycation end products under the influence of RA was previously presented in vitro and in vivo [12]. The use of RA in doses of 10 and 50 mg/kg in rats with estrogen deficiency did not affect the body mass. RA administered at a dose of 10 mg/kg of ovariectomized rats did not affect estradiol and progesterone concentrations compared with ovariectomy control rats, whereas RA at a dose of 50 mg/kg of estradiol showed a trend of growth. Orchids containing RA are often used in self-healing and daily diets, so it is possible to consume 5-10 g of these plants daily in the form of infusions and spices [13]. RA is water-soluble, and according to literature data, the efficacy of secretion of this compound in infusions is about 90% [14]. Accordingly, it is possible to consume approximately 110 mg RA daily, i.e., approximately 1.6 mg/kg for adult men weighing 70 kg.