**4. Pharmacokinetics and pharmacodynamics of flavonoids**

#### **4.1 Pharmacokinetic characteristics of flavonoids**

There are several pharmacological functions for flavonoids. However, problems impede their approval as prescription drugs for usage in clinical settings and, to some extent, future research. Plant yield, bioavailability, and low solubility are problems. For 20 years, researchers have studied the metabolism and absorption of flavonoids. The distribution, metabolism, excretion, toxicity, and absorption of flavonoids are not optimal and differ between classes [80]. Flavonoids' in vivo concentration is decreased by their low oral absorption. Low solubility, little oral absorption, and significant phase-I and phase-II hepatic enzyme metabolism. Chemical interactions between bacteria and small intestine epithelial cells affect flavonoid absorption due to intestinal metabolism. In small-intestine epithelial cells, flavonoids are glucuronidated, O-methylated, and sulfated, which reduces their bioactivity [81–84]. In rats, only 20% of oral quercetin was absorbed; the rest was converted to CO2 and excreted in the feces. Within 48 hours, the body excretes absorbed quercetin [85]. The PK profile of flavonoids in plants is influenced by light, temperature, oxygen exposure, pH, and UV radiation. The synthesis of plant flavonoids can be altered by UV light. Flavonoids' extraction and shelf-life are influenced by temperature. 45 to 60°C are ideal for extracting flavonoids from the tissue of the pericarp of litchi fruit [86, 87].

It is challenging to link a single flavonoid molecule to pharmacological action since flavonoids are available as a plant extract that includes several plant natural components. The PK profile of certain flavonoid changes, such as methylation and glycosylation, can be improved. In the next section, we shall talk about how methylation and glycosylation impact the pharmacokinetics and bioavailability of flavonoids. Derivative of Flavonoids with Better PK Properties [88, 89]. Their chemical structure governs the bioavailability and chemical stability of flavonoids [90–92].

Absorption, distribution, and metabolism are all impacted by changing the flavonoid skeleton. Methylation, which is the process of adding a methyl group to a substrate, controls cellular energy, epigenetics, and gene expression [93, 94]. Methylated flavonoids, which get a methyl group through the hydroxyl group, and Cmethylated flavonoids, in which the methyl group is directly attached to the C atoms of the basic skeleton, are two different types of methylation flavonoids, depending on the location. OMT and CMT catalyze the methylation of O and C, respectively (CMT). SAM provides the methyl group through a biomolecular nuclear substitution (SN2) procedure. The first SAM-dependent methyltransferase to crystallize is catechol-OMT [95, 96]. Methylated flavonoids outperform their non-methylated analogs in terms of stability, potency, and bioavailability. Chemical characteristics, immunogenicity, and PK/PD are all influenced by glycosylation. To increase solubility, stability, and toxicity, flavonoids can be glycosylated to produce O- or C-linked glycosides. Glycosylated flavonoids can either be O-glycosides or C-glycosides, depending on the glycosidic connection to the basic flavonoid skeleton. While the sugar molecule in C-glycosides is *Flavonoids Biosynthesis in Plants as a Defense Mechanism: Role and Function Concerning… DOI: http://dx.doi.org/10.5772/intechopen.108637*

connected to the basic flavonoid skeleton by its respective carbon atoms (generally at C-6 and C-8 positions), the sugar moiety in O-glycosides is coupled to the basic skeleton by a hydroxyl bond (commonly at 3-C and 7-C positions) [54, 89, 97]. Glycosylation often occurs in the subclasses of flavones and flavanols. Rutin and hesperidin are two flavonoids that do not dissolve well in water or alcohol. In nonpolar solvents, non-glycosylated flavonoids (glycans) dissolve. Glycosylation increases the chemical stability of flavonoids in vitro. The stability of glycosylated flavonoids is increased, making them promising. A few glycosylated flavonoids, including luteolin-40 -O-glucoside and apigenin-7-glucoside, also inhibit BCRP [1, 73, 98]. Glucosylated were mostly used as examples to keep the effects of glycosylation easy to understand.

#### **4.2 Pharmacodynamics of the polyphenolics**

The major concern of several studies was the regulatory effects of polyphenolics on the human body to understand the Pharmacodynamics mechanism [99–105]. The current study investigates the effect of 14 polyphenolic compounds from the sponge, and the pharmacodynamics of the 14 compounds were listed and investigated according to ADME (Adsorption, Distribution, Metabolism, and Excretion). Not all bioavailable compounds are physiologically active. Furthermore, polyphenolic compounds' pharmacodynamics are not linked to their physiological activity [84]. For that, many studies were established to discover how common polyphenolics' pharmacodynamics, especially flavonoids, correlate with their inhibitory activities. The polyphenolic bioavailability profiles are classified into subgroups; for example, isoflavones consider the most absorbed type of flavonoids, followed by quercetin. The previous study indicates that the amounts of these compounds in plasma (after intestinal and hepatic metabolism) are very low, indicating their most flavonoids were eliminated rapidly [106]. Quercetin administered significantly inhibited platelet function and signaling in vivo studies. Physiological effects of flavonoids correlate with structural features of these compounds; there is also evidence to show that flavonoid dynamics in vivo are likely to be complex. Also, flavonoids can reduce the pathological effects of atherosclerosis, thrombosis, and CVD risk, while flavonoid bioavailability has been researched extensively [107, 108]. Quercetin is one of the most important plant molecules that has shown many pharmacological activities, such as being anticancer, antiviral, and treating allergic, metabolic, and inflammatory disorders, eye and cardiovascular diseases, and arthritis [109]. It has also shown a wide range of anticancer properties, and several reports indicate its efficacy as a cancer-preventing agent. Quercetin also has psychostimulant properties and has been documented to prevent platelet aggregation, capillary permeability, and lipid peroxidation and enhance mitochondrial biogenesis. Gallic acids mainly involved MAPK and NF-κB signaling pathways. It thus greatly reduced the inflammatory response by decreasing the release of inflammatory cytokines, chemokines, adhesion molecules, and cell infiltration [110, 111]. Thus the main Pharmacological activities and pharmacodynamics mechanism of Gallic acids were associated with anti-inflammatory effect. Pyrogallol is mostly used in pharmaceutical companies for medicinal purposes as a topical antipsoriatic. Pyrogallol showed both prooxidant and antioxidant activities. Additionally, Pyrogallol act as an antimicrobial activity by generating reactive oxygen species and is critical for its [112, 113]. Kaempferol has been confirmed to hurt cancerous cells of different types by triggering apoptosis, cell cycle arrest at the G2/M phase, downregulation of signaling pathways, and phosphoinositide 3-kinase (PI3K)/protein

kinase B (AKT). Kaempferol also induces the activation of cysteine proteases involved in apoptosis initiation, preventing the accumulation of reactive oxygen species (ROS) in cancer development [114]. coumarin has previously reported a wide range of pharmacological activities, such as anticancer, anti-inflammatory, antioxidants, anticoagulant, and antibacterial [115]. Phenolic acids have two types: hydroxybenzoic acids, such as gallic, and hydroxycinnamic acids, such as ferulic, caffeic, and ocoumaric acid. o-Coumaric acid is a hydroxycinnamic acid with different biological activities, such as anti-lipidemic, antioxidant, and anti-carcinogenic [116]. Furthermore, the therapeutic effect of o-Coumaric acid in a human breast cancer cell line (MCF7) treatment through CYP isozymes mRNA levels was reported by Sen et al. [117], that studied the effect of o-Coumaric acid on drug-metabolizing CYP enzymes at the mRNA and protein expression levels was investigated in a human hepatocarcinoma cell line (HepG2 cells and that also confirmed in the current study as the extract exhibit cytotoxicity against HepG2 with 41.2 ug. Hydroxycinnamic acids (HCAs) (coumaric acid, ferulic acid, caffeic acid, and Chlorogenic acid) in general and Chlorogenic acid acids specifically are of high importance due to their beneficial pharmacological effects [118]. HCAs are mainly recognized as potent antioxidants and have a diverse therapeutic effect against various diseases, for example, cardiovascular and neurodegenerative diseases and cancer Anti-inflammatory and antimicrobial activities. Ferulic acid inhibited the synthesis of TNF-alpha and decreased, Ferulate, their antioxidant mechanism of action through maintaining redox regulation, suppressing NF-κB activation, and modulating the expression of NF-κB-induced, proinflammatory such as COX-2 and iNOS [50]. Also, the NF-kB suppression by Ferulate is mediated via suppressing the activation of NIK/IKK and MAPKs. Caffeic acid inhibits the activities of COX-1 and COX-2 enzymes and inhibits prostaglandin synthesis and COX. Caffeic acid also decreased several inflammatory cytokines such as interleukin (IL)-beta, IL-6, and tumor necrosis factor (TNF)-. Chlorogenic acid has an antidiabetic and anti-obesity role and significantly decreases the level of cholesterol and triacylglycerol [119]. The same effect was observed with ferulic acid as the mechanism of action of ferulic involved the suppression and/or down-regulation of lipid metabolism genes [120]. Additionally, chlorogenic acid significantly elevated beta-oxidation and lipase activity in diabetic animals. The catechol has an antiinflammatory role through inhabiting the NF- κB, and TNF- α [50].
