**2. Bioavailability, absorption, and adjuvant interactions of melatonin**

Its amphiphilic character allows melatonin to penetrate all compartments of a cell because, helped by its small size, conferring a good solubility in both water and lipids. Melatonin and its derivatives have antioxidant ability and can start a radical scavenger cascade creating oxidation products (e.g., hydroxymelatonin) that help to eliminate oxygen reactive species [11]. Due to this, melatonin is effective and bioable in organisms [12]. Herbs that have been used in traditional Chinese medicine have up to several thousands of melatonin nanograms in their tissues [13], implying a decent source of the neurohormone. It was also measured in several parts, however, in seeds where the highest levels have been found, probably related with the needs of reproductive organs (e.g., defend from adversarial attacks), fluctuations of melatonin concentration are even in varieties of the same species [14]. While animals can only obtain melatonin from food, plants can synthesize it or absorb and accumulate it from the environment [15]. Eating foodstuffs rich in melatonin can increase melatonin serum concentration [16]. Organs that produce melatonin (e.g., pineal gland, retina [17], and gastrointestinal tract) can also process it from foodstuffs [18].

#### **2.1 Bioavailability**

Melatonin bioavailability from formulations and food ranges from 2.5% to 33% [19, 20] and with protein binding of 60% measured *in vitro* [21]. Oral administration of melatonin has been described as a proper absorption, extensively distributed, and potentially completely metabolized in humans [22]. Its receptors are widely distributed, and melatonin quickly penetrates the blood-brain barrier [23]. Considering that, it would be expected that melatonin from dietary sources would also likely be absorbed. Despite this may be accurate, melatonin uptake from herbal remedies or products and phytomelatonin (melatonin in plants) oral bioavailability have not been highly explored, except for St. John's wort. Thirteen participants were treated with a hydroethanolic extract of dried flowering tops or aerial parts of St. John's wort, and that significantly improved the nocturnal melatonin serum levels [24]. However, this study has the limitation of ignoring extract melatonin concentration or dose taken.

*Food as a Dietary Source of Melatonin and Its Role in Human Health: Present and Future… DOI: http://dx.doi.org/10.5772/intechopen.103969*

Regarding oral bioavailability in the experiments with chicks, we know that when feeding them with edible plants rich in melatonin, circulating melatonin levels increase, and it is proven that this melatonin is functional as it competed with melatonin binding sites in the brain.

In humans, serum melatonin levels have been assessed after beer intake. This study assessed 18 brands of beer, containing up to 170 pg/mL, males (n = 7) received 660 mL, and females (n = 3) 330 mL. Consumption resulted in an increase of 112 ng and 56 ng of melatonin, respectively, related to the volume taken, confirmed by serum analysis by ELISA prior and 45 min after the beverage [25]. Also in humans, serum melatonin raised from 10 to 12 pg/ml 60 min after a glass of 100 ml of red wine was drunk [26]. Melatonin bioavailability is also high in case of taking fruits, as a study with 12 volunteers consuming for breakfast a juice from either orange, pineapple, or bananas containing 302 ng, 150 ng, and 1.7 ng of melatonin, respectively, increasing melatonin in serum. Blood tests were carried out before juice and then hourly the next 3 hours. ELISA proved that serum melatonin concentration nadir was at hour 2 after breakfast. All values were significantly increased from time zero for pineapples (146 vs. 48 pg/mL, p = 0.002), oranges (151 vs. 40 pg/mL, p = 0.005), and bananas (140 vs. 32 pg/mL, p = 0.008) [27]. Further, an across ages study with three groups of participants (20 ± 10, 45 ± 10, and 75 ± 10 years old) reported after 5-day intake of 200 ml/day of grape juicehigher antioxidant capacity [28], as well as 6-sulfatoxymelatonin in urine [29].

#### **2.2 Pharmacokinetics**

Melatonin suffers great hepatic metabolism upon oral intake, with high hepatic first-pass effect [30, 31], which explains its low bioavailability [31]. Animal and human studies describe that melatonin metabolism mainly occurs through CYP1A2 and CYP2C19 hepatic enzymes [30, 32]. 6-Hydroxy-melatonin is conjugated with sulfate and forms the most abundant metabolite (80%): the 6-sulfatoxymelatonin (6-SM) [30, 33]. Then 6-SM metabolite can be measured in urine as an inactive metabolite [34]. Hence, further research is needed in human metabolites as some works have described the existence of active metabolites excreted [30].

#### **2.3 Adjuvant interactions**

The co-ingestion of melatonin-rich food with phenolic compounds (caffeic acid or quercetin) could increase its bioavailability [35]. When analyzing the relation of cherries with sleep cycle and urinary 6-hidroxymelatonin sulfate (MT6), it was observed that regardless of melatonin absence in some cherry varieties (Ambrunes had only 37.6 ± 1.4 ng of serotonin in 100 g fresh fruit [36]), an increase of urinary MT6s was detected [37, 38]. Thus, it was possible to infer that both MEL and serotonin present in cherries may have contributed to improvements in sleep parameters and MT6 excretion [37, 38].
