**4. Bioavailability and metabolism**

Bioavailability of isoflavones is based on data from absorbtion, metabolism, distribution and excretion studies. After the intake of pure compounds, isoflavone‐rich extracts or foods containing high levels of isoflavones, the parent compound and their metabolite can be found in plasma and urine of human volunteers. Following ingestion, soy isoflavones attain maximal plasma concentration within 4–8 h and then eliminate from the body through the bile and kid‐ neys with an elimination half‐life that is on average 8 h [23, 24]. Aglycones are well absorbed due to their low water solubility and small molecular weight [25]. After ingestion, isoflavone glyco‐ sides are hydrolyzed by intestinal glucosidases, which partially release the aglycones daidzein, genistein and glycitein [24]. These may be absorbed or converted to a number of metabolites including equol and p‐ethyl phenol [24].

It was proved that intestinal microflora plays an important role in the metabolism and bioavailability of isoflavones [26]. It is considered that about 50% of Asians and 25% of non‐ Asians host the intestinal bacteria that convert daidzein into the isoflavonoid equol [27]. Variation in individual metabolism of phytoestrogens due to differences in gut microflora might influence the serum concentration of phytoestrogens. It was found that the capacity to produce equol is higher among Japanese and Korean men than among American men [28]. After an intake of 50 mg isoflavone, the urinary excretion was 42% for daidzein and 16% for genistein [29]. Fermented soy products, or supplements in which the soy extract has been hydrolyzed, contain mostly the aglycone forms of isoflavones; however, following ingestion, the plasma profile of isoflavone metabolites is the same, no matter the form ingested [30]. Free aglycones, released after hydrolysis, are absorbed by passive diffusion across the intestin [31].

The extensive metabolization of the aglycones is evident in the extremely low content of the free form in body fluids, of less than 1% in human plasma and urine [32]. The metabolization of genistein has intensively been studied and thoroughly reviewed [25]. Following the faith of most xenobiotics, it undergoes detoxification, being conjugated to glucuronides and sulfates. Among them, monoglucuronides are present in the highest proportion (62.5%), followed by diglucuronides, sulfoglucuronides, disulfates and monosulfates in human urine after dietary intake of soy products [33]. The percentage of sulfates was reported to be slightly higher in blood (20%) than in urine (13%) [32]. In humans, the plasma level of genistein (all forms) is situated in the micromolar range, while the level of free genistein is in the higher nanomolar range. The rate of metabolization after oral ingestion is less than half an hour, with conjuga‐ tions occurring in the intestine, the liver but as well in the kidneys, heart and lungs. The tissue distribution of genistein is highest in the gastro‐intestinal tract and liver, consistent with its enterohepatic recycling [34]. While the differences between individuals are very high, the oral bioavailability of genistein is low due to extensive metabolization and high expression level of efflux transporters (such as breast cancer resistance protein (BCRP)) [25].
