Flavonoids are naturally occurring secondary metabolites that can be obtained from various plant parts such as fruits, vegetables, roots, stems, flowers (Zheng et al., 2025). They function in plants as light filters, visual attractants, feeding repellents, antioxidants, antimicrobials, and photoreceptors (Pietta, 2000). These properties underpin their wide applicability in cosmetics and medicine (Kurek-Gorecka et al., 2020). Flavonoids also have diverse therapeutic applications in humans due to their antioxidant, anticancer, antiviral, anti-inflammatory, and anti-allergic properties (Pietta, 2000; Chavda et al., 2022). Chemically, flavonoids are the polyphenolic compounds that can be classified as flavanols, isoflavonoids, anthocyanidins, flavones, and flavonols (Figure 1) (Panche et al., 2016).

Flavonoids are widely being recognized as potent anticancer agents that exert their effects through various mechanisms, including scavenging of reactive oxygen species (ROS), promoting apoptosis, inducing cell cycle arrest, anti-angiogenesis, and inhibiting the proliferation and invasion of cancer cells (Pietta, 2000; Rana and Mumtaz, 2025). The hydroxyl groups present in flavonoids are primarily responsible for their therapeutic activities, particularly their antioxidant and ROS-scavenging properties (Vo et al., 2019). Consumption of a flavonoid-rich diet is reported to decrease the cancer risk in various studies (Rodriguez-Garcia et al., 2019; Chavda et al., 2021; Khan et al., 2021; Parmenter et al., 2025). Moreover, various flavonoids, including quercetin, kaempferol, and morin, effectively modulate cancer cell chemoresistance by inhibiting efflux transporters such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs), thereby enhancing intracellular drug accumulation and restoring drug sensitivity (Liskova et al., 2021). Additionally, flavonoids modulate resistance-associated signaling pathways, including nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription 3 (STAT3), thereby influencing cell survival, apoptosis, and DNA repair mechanisms (Bukowski et al., 2020; Tian et al., 2023; Mir et al., 2024). Figure 1 briefly captures various inhibitory anticancer mechanisms elicited by various flavonoids, in general.

Despite immense therapeutic potential, the unfavorable pharmacokinetic properties of flavonoids limit their use in clinical settings (Hussain et al., 2025). Most flavonoids exhibit poor water solubility, low oral absorption, and undergo extensive first-pass metabolism, resulting in limited systemic bioavailability (Halevas et al., 2022). These pharmacokinetic challenges necessitate the development of innovative delivery systems such as nanoparticles, liposomes, and solid lipid carriers to enhance their stability, absorption, and targeted delivery of flavonoids (Billowria et al., 2024; Hu et al., 2025). Nanoparticle system loaded with flavonoids is reported to increase the drug retention time, thereby enhancing their circulation time and stability at a lower drug dose (Sharma et al., 2022; Abdi Syahputra et al., 2024; Rana and Mumtaz, 2025). Furthermore, structural modification using a prodrug strategy has been explored to introduce favorable physicochemical properties that enhances chemical stability and target specificity of flavonoids (Zhao et al., 2019; Dehelean et al., 2022). Recently, an apigenin prodrug has been synthesized, which exhibited increased stability and cytotoxic potential as compared to the parent compound apigenin (Diamantis et al., 2023). In another study, conjugation of quercetin with amino acids is reported to increase the solubility, stability, cellular permeability, as well as anticancer activity (Dobrydnev et al., 2020). Overall, the expanding field of flavonoid pharmacology now bridges traditional phytomedicine with modern drug development tools, paving the way for clinically translatable anticancer therapeutics (Abdi Syahputra et al., 2024). This article emphasizes the exploration of the aforementioned parameters to ensure the therapeutic efficacy and safety of flavonoids in cancer treatment and management. Flavonoids are highlighted as potent natural anticancer agents with diverse mechanisms but limited clinical applications due to poor pharmacokinetics. Emerging drug delivery systems and prodrug approach aim to bridge the gap.

Rather than a catalog, this review is organized around translation bottlenecks (exposure, selectivity, and safety) and how modern solutions shrink them. Nanoparticle and nanogel carriers consistently raise bioavailability and tumor deposition while reducing off-target exposure; prodrugs and methyl/glycosyl edits rebalance permeability-metabolism tradeoffs; and drug-drug interactions (DDI)-aware scheduling mitigates CYP3A4-linked risks. We map each mechanistic promise (for example, tumor microenvironment (TME) reprogramming, efflux modulation) to an ADME (absorption, distribution, metabolism, and excretion)-compatible formulation and a clinical next step (PK/PD (pharmacokinetics/pharmacodynamics) markers, combo logic), emphasizing 2024–2025 advances (Dewanjee et al., 2023; Abdi Syahputra et al., 2024; Kondža et al., 2024; Hu et al., 2025; Liga and Paul, 2025).

Cancer remains one of the leading causes of chronic disease-related deaths worldwide, accounting for nearly 10 million deaths in 2020, according to the World Health Organization (WHO). Cancer is characterized by the uncontrolled growth of cells, and can be cured if diagnosed at an early stage (Mathur et al., 2015). Currently, cancer is treated using chemotherapy, surgery, radiation therapy, immunotherapy, endocrine therapy, and targeted therapy. Among these, immunotherapy remains a promising but challenging approach. Side effects associated with cancer chemotherapy, such as immunosuppression, drug resistance, and systemic toxicities, limit the scope of chemotherapeutic agents (Aslam et al., 2014). Surgery and radiation therapy are used to treat a specific tumor or an area of the body (Baskar et al., 2012). Surgical resection causes physical pain to the patients as well as impairs the normal functioning of surrounding tissues (Jain et al., 2014; Chen et al., 2022).

In clinical practice, surgery and chemotherapy are the most commonly used treatments for cancer; however, cancer cells often develop resistance to anticancer drugs over time. Drug resistance is responsible for 90% of chemotherapy failures (Davodabadi et al., 2023). Cancer cells develop resistance to cytotoxic drugs through multiple complex mechanisms, which can be intrinsic or acquired. Intrinsic resistance refers to the inherent ability of cancer cells to withstand therapeutic interventions even before treatment begins. This resistance is heterogeneous and may arise due to inherited genetic mutations that render tumor cells less responsive to chemotherapeutic agents, pre-existence of unresponsive cancer stem cells or activation of intrinsic pathways that can remove or decrease the intracellular concentration of drugs. On the other hand, acquired resistance emerges during treatment and is typically attributed to the development of drug-resistant cancer cell populations that often contain secondary genetic alterations, ultimately leading to therapy failure. Multiple mechanisms have been implicated in acquired resistance, including modulation of TME, alteration in DNA repair mechanisms, dysregulation of transmembrane transporters that reduced intracellular drug concentrations, epigenetic and epistatic modifications, inactivation of drug due to metabolism, and mutations in drug targets (Michael and Doherty, 2005; Eslami et al., 2024; Khan et al., 2024). This critical issue can ultimately result in disease recurrence, treatment failure, and increased mortality. Figure 2 illustrates the diverse factors contributing to drug resistance in cancer. Cancer drug resistance arises from both intrinsic and acquired mechanisms, complicating treatment and contributing to therapy failure. This underscores the need for alternative or adjunctive approaches.

The TME comprises a complex and dynamic network of non-malignant cells, blood and lymphatic vessels, lymphoid organs, and metabolites. TME plays a critical role in the recruitment of non-transformed cells, leading to intercellular communication via the release of signaling molecules such as cytokines (Figure 3). Wound healing is another critical process in TME that contributes to oncogenic signaling and promotes tumorigenesis (Jin and Jin, 2020). The TME is a complex ecosystem, particularly enriched with various immune components, making it a critical target for cancer therapy. For example, T-cells have been central to the development of immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. Additionally, the TME hosts multiple innate immune cells, including myeloid-derived suppressor cells (MDSCs) and natural killer (NK) cells, which are modulated by cytokine signaling and can either support immune surveillance or contribute to immune dysfunction, ultimately leading to tumor progression. Given this complexity, a thorough understanding of the immune landscape of the TME is essential for the development of effective immunotherapeutic strategies (Hinshaw and Shevde, 2019).

In addition to its cellular and molecular components, the TME plays a critical role in regulating epithelial-mesenchymal transition (EMT). During cancer progression and invasion, tumor cells interact with diverse components of TME that switch their phenotype while losing epithelial features. This process helps in the acquisition of mesenchymal and stem cell-like traits that significantly enhance invasiveness and metastatic potential. Evidence reports that TME assists EMT through various signaling pathways and cellular interactions (Suarez-Carmona et al., 2017). Among the various signaling molecules, transforming growth factor-beta (TGF-β) is a key EMT inducer in mediating this process (Yu et al., 2013; de Visser and Joyce, 2023).

Angiogenesis is another crucial TME-regulated mechanism required for advanced cancer progression and metastasis. Angiogenesis ensures a continuous supply of oxygen and nutrients to rapidly growing tumors, thereby facilitating tumor dissemination (Quail and Joyce, 2013). Immune cells present in TME actively contribute to angiogenesis by releasing pro-angiogenic factors that facilitate tumor vascularization. During intravasation and extravasation, macrophages play a significant role in promoting tumor vascularization and facilitating the penetration and traversal of tumor cells across vascular barriers. In systemic circulation, platelets protect tumor cells from immune recognition and channel them to the extravasation site. Additionally, MDSCs and NK cells accumulated in pre-metastatic and metastatic niches support tumor cell dissemination and colonization through modulation of immune responses (Quail and Joyce, 2013). Thus, the TME significantly influences cancer progression via EMT, angiogenesis, and immune modulation. Understanding its complexity is crucial for targeted therapies.

Flavonoids are a group of natural compounds with variable phenolic structures. Chemically, flavonoids are based upon a 15-carbon skeleton made up of two benzene rings, referred to as “ring A” and “ring B” respectively (Figure 4) (Sharma et al., 2019). Heterocyclic pyran “ring C” further connects these rings. Interestingly, “isoflavones” are flavonoids with “ring B” linked to “position 3” of “ring C”. The term “neoflavonoids” refers to phytocompounds where “ring B” is connected in the fourth position of “ring C”. Additionally, linking of “ring B” at “position 2” causes the classification of flavonoids into several groups, including flavones (such as luteolin and apigenin), flavonols (such as quercetin, myricetin, and kaempferol), flavanones (such as naringenin and hesperetin), and flavan-3-ols (such as catechin and epicatechin) (Ignat et al., 2011). Generally, the degree of oxidation and the pattern of “ring C” placement vary among distinct types of flavonoids (Figure 5). In contrast, the diversity of specific compounds within a given class of flavonoids is primarily determined by the substitution patterns on rings A and B (Panche et al., 2016). Thus, flavonoids share a common phenolic skeleton but differ structurally, influencing classification and biological activity. Structural diversity underpins their varied anticancer roles.

Numerous chemotherapeutic agents are available in the market for the treatment of cancers, and several are in the development phase. However, the side effects associated with the non-selectivity towards tumor cells of clinically-used chemotherapeutic agenst have limited their widespread use. These limitations have encouraged research on natural products, which are considered much safer than synthetic agents and have traditionally been used to combat cancers for decades (Demain and Vaishnav, 2011; Khan et al., 2021). Several epidemiological studies documented the reduced risk of cancer by consuming a diet rich in fruits and vegetables (Key, 2011; Wu et al., 2019), which is primarily considered due to the presence of flavonoids. The anticancer potential of flavonoids is attributed to the modulation of enzymes and receptors involved in the signal transduction pathways related to cellular differentiation, proliferation, apoptosis, angiogenesis, metastasis, and reversal of multidrug resistance (Ravishankar et al., 2013). The beneficial effects of flavonoids in cancers are attributed to their antioxidant, immunomodulatory, and anti-inflammatory properties. Natural flavonoids shows anticancer effects by modulating signaling pathways, reducing oxidative stress, and reversing drug resistance. Their safety profile makes them attractive alternatives to synthetic agents.

While quercetin, apigenin, and kaempferol dominate historical discussion, several less-covered subclasses now show compelling anticancer signals together with formulation paths that address exposure limits. Below we highlight four such leads and outline mechanisms, ADME opportunities, and near-term study designs.

Numerous epidemiologic studies have demonstrated that certain flavonoids, as well as diets or foods rich in flavonoids, are beneficial in preventing cancer development and its progression. Moreover, flavonoids reduce the established high-risk indicators associated with cancer (Baby et al., 2021). However, additional clinical trial studies are required to assess the efficacy of flavonoids in people with a range of characteristics, including age, gender, disease severity and stage, prior treatment history, and comorbid medical conditions (Kikuchi et al., 2019).

Flavonoids, like those found in tea and coffee, are consumed worldwide, and several research studies have demonstrated their positive benefits on human wellbeing, including their ability to prevent cancer. According to an analysis by Yang and Hong of case-controlled and prospective cohort studies that were published in 2008, the consumption of green tea reduced the cancer risk in 39 cases of colon, breast, esophageal, kidney, lung, ovarian, pancreatic, stomach, and prostate cancers, whereas 46 cases indicated no risk reduction. These observations imply that green tea may help to avoid certain cancers (Yang and Hong, 2013; Suzuki et al., 2016; Hayakawa et al., 2020). Therapeutic potential of flavonoids significantly differs with various factors like age, gender, and disease state. Geriatric patients exhibit enhanced benefits due to increased oxidative stress patterns but decreased bioavailability from various metabolic changes with age-related factors. The flavonoid’s phyloestrogenic activity is associated with various gender differences. In the cases of various disease states like diabetes/inflammation may enhance the antioxidant effects of flavonoids by making a mediation in gut microbiota-mediated metabolism. Such factors as age, gender, and diseases need to be considered for flavonoid-based therapeutic approaches (Del Rio et al., 2013; Fraga et al., 2019; Favari et al., 2024; Hu et al., 2025).

To assess the effectiveness of flavonoids in cancer therapy, Bisol et al. looked at some clinical trial studies (Phases II and III). The U.S. Food and Drug Administration (FDA) states that phase II clinical studies are carried out to evaluate a medicine’s effectiveness in treating an illness, and phase III studies are carried out to confirm that a possible drug is superior to the gold standard treatment option. In all, 1 phase III and 22 phase II clinical trials that employed flavonoid compounds as a single entity or in combination with other therapies to treat lymphoid cancer that were published by January 2019 were chosen for study. It was shown that flavopiridol is the most frequently administered flavonoid compound (at a dose of 50 mg/m² IV) for most of the cases. Flavonoids demonstrated sophisticated positive consequences for lymphoid and hematopoietic tissues than for solid tumors (4 patients with complete response (CR) and 21 with partial response (PR) among 525 patients in 12 trials), despite the relatively low rate of CR or partial response PR with any administration protocol (Bisol et al., 2020). Some of the flavonoids whose anticancer potential in human subjects has been evaluated or are currently under investigation have been summarized in Table 2. 60 trial entries spanning ∼17 flavonoid categories/combos are covered where the most studied agents are catechin, genistein, quercetin, and EGCG. While there was strong emphasis on prostate malignancies followed by multiple studies related to breast, lung, bladder, colon/colorectal, and skin cancer, there were trials related to ovarian, cervical, esophageal, kidney, head and neck premalignancy, glioma/glioblastoma, multiple myeloma, and follicular lymphoma. When considering the phase trials status, predominantly phase 2, with some phase 1/early phase 1, and only a handful of phase 3 studies. Further, studies include purified flavonoids, botanical preparations, and drug-flavonoid combinations, reflecting an adjunct/chemo-sensitization emphasis. While epidemiological studies and early-phase trials suggest promise, clinical outcomes remain variable and context-dependent. More large-scale, controlled studies are needed.

Here we summarize what currently limits oral/systemic exposure for flavonoids and which delivery/chemistry knobs reliably move the PK needle. Once flavonoids are taken orally, it becomes crucial to comprehend their pharmacodynamics. Additionally, it is beneficial to analyse the available structure-activity relationship (SAR) data to identify the pharmacological activities associated with flavonoids. In conjunction with SAR attributes, the pharmacokinetics, biotransformation, and metabolism of flavonoids play a significant role in determining their pharmacological effects. Further investigation is required to elucidate factors such as absorption rate, pharmacokinetics, metabolite characterization, and the physiological effects of these metabolites to establish a correlation between the SAR of flavonoids and their impact on human nutrition and medicine. Flavonoids are commonly found in food items in the form of O-glycosidic compounds, which are conjugated with glucose, glucorhamnose, arabinose, galactose, or rhamnose units (Hammerstone et al., 2000). When checked on PubMed using search terms including flavonoid, ADME, and cancer, it yielded 67 articles. We read the abstracts of each of these articles and then selected studies relevant to this theme.

The β-linkages in these sugars make them resistant to hydrolysis by pancreatic enzymes. However, the process of β-hydrolysis is carried out by specific intestinal microbiota. Such microbiota include Peptococcus, Peptostreptococcus, and Clostridia, which ferment these sugars in the colon (Cummings and Macfarlane, 1991). Specific enzymes like lactase, phlorizin hydrolase, classified as β-endoglycosidase, are known to deglycosylate flavonoids, creating sites for conjugation (Leese and Semenza, 1973; Day et al., 2000). Flavonoids such as quercetin-3-glucoside, luteolin-7-glucoside, and kaempferol-3-glucoside are absorbed and hydrolyzed in the small intestine through the action of β-glucosidases (Gopalan et al., 1992).

Flavonoids, a diverse group of compounds known for their abundance and potency, have been extensively studied to gain insights into their absorption and metabolism (Hollman et al., 2009). The absorption kinetics of flavonoids can vary significantly due to different sugars and functional groups in the flavan nucleus. Several factors, including dosage, administration route, vehicle of administration, colon microbiota, diet, food matrix, and sex differences, contribute to the variability in flavonoid absorption (Erlund, 2001).

In addition to the hydrolysis of flavonoid glycosides, the cecal microflora also plays a role in breaking down monomeric flavonoids into monophenolic acids. For instance, intestinal bacteria can cleave the C3-C4 bond of the heterocyclic structure, resulting in the production of quercetin metabolites such as 3,4-dihydroxy-phenylacetic acid and phloroglucinol (Winter et al., 1991).

A previous study revealed that rats exposed to rutin produced specific compounds, including 3,4-dihydroxytoluene, phenylacetic acids, and 3-(m-hydroxyphenyl) propionic acid, in their urine (Baba et al., 1983). The hydrolysis of rutinosides (quercetin-3-rutinoside) by colonic microflora was found to be more significant compared to quercetin glycoside (quercetin-3-glucoside), explaining the lower bioavailability of rutin observed in human studies (Olthof et al., 2000). In human subjects, the absorption of quercetin in the small intestine was found to increase to 52% when a glucose unit was present in the molecular structure, compared to 24% for the aglycone unit and 17% for rutin-based compounds. This increase in absorption suggests that quercetin glucoside facilitates interaction with epithelial glucose transporters, leading to a more rapid uptake and improved bioavailability of glucosides following ingestion (Gee et al., 1998).

The biodegradation of larger flavone molecules into more minor, low molecular weight compounds is necessary to cross the intestinal epithelium. According to Déprez et al., dimers and trimers of procyanidin can move across the epithelium of the small intestine. Since these molecules typically consist of (+) catechin and (−) epicatechin subunits, catechins are likely the primary by-products of degradation (Déprez et al., 1999). The bacterial colony facilitates this degradation process in the cecum, and the lower pH in the stomach (Spencer et al., 2000; Groenewoud and Hundt, 2009). The hydrolysis of proanthocyanidin oligomers into catechin dimers and free catechins takes approximately 3.5 h in the gastric environment. After three catechin units, the degradation rate increases proportionally to the degree of polymerization. Although it has been suggested that catechins are responsible for the pharmacological effects of proanthocyanidins with high molecular weight, the duration of 3.5 h or more exceeds the average human gastric emptying rate of 30–90 min. Therefore, the influence of acid hydrolysis is undoubtedly less significant than subsequent metabolic processes (Winter et al., 1991).

In a study carried out by Doostdar et al., it was discovered that the flavones acacetin and diosmetin possess the ability to inhibit the ethoxy resorufin O-dealkylase (EROD) activity of two specific cytochrome P450 enzymes, namely CYP1B1 and CYP1A. The selectivity of these enzymes was primarily influenced by substitutions at the 3′ and 4′ positions of the flavonoid structures involving hydroxy and/or methoxy functional groups. Interestingly, other flavonoids such as naringenin, eriodictyol, and homoeriodictyol exhibited poor inhibitory effects on human CYP1A EROD activity (Doostdar et al., 2000).

Hesperetin and homoeriodictyol were found to perform O-demethylation of hesperetin to produce eriodictyol in both human CYP1A1 and CYP1B1. Furthermore, homoeriodictyol demonstrated the ability to inhibit human CYP1B1 selectively. It was observed that hesperetin could not be metabolized by human cytochromes CYP1A2 or CYP3A4. In vitro studies using human liver and intestinal microsomes indicated that luteolin primarily undergoes glucuronidation at the seventh position in liver cells. In contrast, in intestinal cells, it occurs at the third and fourth positions. The conjugation of luteolin with intestinal microsomes was approximately three times more prevalent than with liver microsomes. Individual testing of the enzymes revealed variations in the efficiency of glucuronidated luteolin, with certain forms displaying higher efficiency than others (Hostetler et al., 2017).

A recent study by Semwal et al. revealed that specific structural features of myricetin, such as the C2 and C3 double bond, the aromatic ring B at position C2, and the hydroxy groups in ring B, may contribute to its cytotoxic properties (Semwal et al., 2016). Previously, it was believed that quercetin was excreted in feces due to its inability to be absorbed in the intestine. However, another research by Murota et al. demonstrated that quercetin is absorbed in the intestine and converted into metabolites (Murota et al., 2002). The transportation of these quercetin metabolites involves the lymphatic system, as observed in a study (Terao et al., 2008).

Furthermore, a study by Moon et al. indicated that females’ regular consumption of onions leads to the accumulation of quercetin metabolites in the bloodstream and various tissues. Specifically, after 1 week of treatment, the total plasma concentration of these metabolites reached 0.6 μM. Rutin exhibits limited bioavailability, which hinders its biological effectiveness. Several drug delivery systems have been developed to overcome this challenge and enhance rutin’s bioavailability (Moon et al., 2000). These systems include nanoparticulate formulations, sulphonation and carboxylation of rutin, enzymatic oligomerization, and cyclodextrin complexation, which improve its aqueous solubility.

Additionally, phospholipid complexation, enzymatic and chemical acylation, and nanoparticulation techniques are employed to enhance the lipid solubility of rutin (Choi et al., 2021). Flavonoids, such as myricetin, kaempferol, quercetin, apigenin, and luteolin, are commonly found in plants and are widely consumed. On average, individuals consume approximately 23 mg/day of these antioxidant flavonoids, surpassing the intake of well-known antioxidants like β-carotene (2–3 mg/day) and vitamin E (7–10 mg/day). Additionally, this intake represents around one-third of the average intake of vitamin C (70–100 mg/day) (Hertog et al., 1993).

Among the various flavonoids, quercetin is the most significant contributor to the dietary consumption of flavonoids. It is predominantly obtained from apples and onions (Knekt et al., 2000; Gibellini et al., 2011). Both preclinical and clinical studies have indicated that quercetin glucosides, cinnamate conjugates, and flavonols are readily absorbed in the small intestine (Olthof et al., 2003; Cermak et al., 2007). However, quercetin galactosides, quercetin, rutin, and naringenin are not absorbed in the intestine. While the exact mechanism of absorption remains unclear, the transport of flavonoids across membranes plays a crucial role in their bioavailability in plants and animals. Further research suggests that ATP-dependent pumps and ATP-independent transporters contribute to this process (Passamonti et al., 2009).

Genistein, an isoflavone, is commonly found in high-soy diets. It has gained significant recognition due to its potential in preventing and treating different cancer types. Many research studies have demonstrated that genistein exhibits anticancer properties, specifically against ovarian cancer. However, its bioavailability, which refers to the amount of the compound that reaches the bloodstream and target tissues, is limited (Lee et al., 2012). Yang et al. conducted mechanistic studies to investigate the factors influencing the ADME of genistein. In terms of absorption, they found that genistein is efficiently absorbed in the small intestine but undergoes significant metabolism in the liver, resulting in lower levels reaching the systemic circulation. The absorption process is influenced by various factors, including the presence of food, the gut microbiota, and the transporters responsible for moving genistein across cell membranes. Regarding distribution, genistein has been detected in various tissues, indicating its ability to reach different target sites in the body. However, its distribution may be affected by factors like protein binding and tissue-specific uptake mechanisms (Yang et al., 2012).

Metabolism studies revealed that genistein undergoes extensive biotransformation in the liver, primarily through phase II enzymes. These enzymes attach other molecules to genistein, making it more water-soluble and facilitating its excretion from the body. Additionally, the gut microbiota also plays a role in the metabolism of genistein. It is primarily excreted through the bile into the feces, with a small portion eliminated in the urine. The researchers highlight the importance of understanding the factors affecting genistein’s ADME to optimize its therapeutic potential and develop effective strategies for its delivery. Understanding these mechanisms is crucial for harnessing the potential health benefits of genistein and developing strategies to enhance its therapeutic efficacy (Yang et al., 2012).

In laboratory studies, flavonoids have shown significant anticancer effects in refractory non-small cell lung cancer (NSCLC) models. However, their effectiveness in clinical applications depends on ADME factors within the body (Manach and Donovan, 2004). Consequently, researchers have recognized the importance of pharmacokinetics as a critical factor in the anticancer properties induced by flavonoids. Investigations have been conducted to assess the ingestion and excretion of flavonoids to understand this aspect (Gugler et al., 1975). The findings from these pharmacokinetic studies, summarized in Table 3, offer valuable insights for guiding effective flavonoid treatments in various types and stages of cancers. Flavonoid absorption, metabolism, and bioavailability are influenced by structural features, gut microbiota, and formulation strategies. Optimizing ADME is essential for clinical translation.

We also outline actionable safety practices-DDI screens (especially CYP3A4, exposure-tuning via delivery, and dose/schedule choices to preserve efficacy while minimizing risk.

Studying the anticancer flavonoids’ PK, drug-likeness, and toxicological properties offers considerable potential for developing new treatments. Because of their antioxidant, anti-inflammatory, and cell-signaling-modulating actions, flavonoids, a varied collection of naturally occurring substances found in plants, have been researched for their potential anticancer qualities. The following are some potential outcomes of studying these issues in the future.

The study results on the pharmacokinetics, drug-likeness, and toxicological characteristics of anticancer flavonoids provide insight into their potential as attractive candidates for cancer treatment. Comprehensive studies have revealed that flavonoids, a group of polyphenolic chemicals abundantly found in various plant sources, have complex PK profiles that affect how quickly they are absorbed, distributed, metabolized, and excreted by the body. The benefits of flavonoids have been emphasized in several studies, including their capacity to regulate various drug-metabolizing enzymes, transporters, and signaling pathways. Because of their adaptability, they have the potential to be used as adjuvants to conventional chemotherapy, enhancing therapeutic efficacy and minimizing side effects through synergistic interactions.

Additionally, the drug-likeness evaluation highlights the structural variety of flavonoids, which have benefits and drawbacks. Although the intricacy of these compounds and their polyphenolic makeup can prevent them from being optimized as conventional small-molecule medicines, novel drug delivery methods and packaging techniques have been developed to overcome these drawbacks. These strategies seek to increase these drugs’ bioavailability, stability, and targeted delivery to tumor locations, increasing their clinical viability (Rosales and Fabi, 2023).

Extensive studies into the anticancer flavonoids’ safety profiles have shown their typically low toxicity and appropriate safety margins regarding toxicological characteristics. However, it is crucial to recognize that their toxicity profiles may be affected by the dose-response relationship, possible drug interactions, and individual variances in metabolism. Determine their long-term safety and potential side effects through rigorous preclinical and clinical testing (Zhang et al., 2020).

The potential flavonoids that have cytotoxic activity, which mainly consist of quercetin, kaempferol, genistein, and epigallocatechin gallate. These compounds possess a wide range of pharmacokinetic advantages when these molecules will be formulated as nanoformulations and also prodrugs that can increase bioavailability. These molecules possess a very favorable ADMET profile and will also be considered for further exploration in anticancer research. On considering the toxicological parameters, these compounds possess less systemic toxicity. Major developments in various drug delivery systems, the in silico ADMET profiling via various computational approaches can improve the safety and efficacy of anticancer flavonoids. On considering all the above facts, flavonoid molecules have a better clinical translational potential as effective anticancer drugs.

The core of the investigation into anticancer flavonoids is the confluence of PK insights, drug-likeness considerations, and toxicological evaluations. Despite the progress that has been achieved, there is still a need for pharmacologists, chemists, toxicologists, and clinicians to work together transdisciplinarily to bridge the gap between laboratory findings and clinical applications. Further studies should concentrate on improving the PK profiles of flavonoid compounds, enhancing their molecular mechanisms of action, and carrying out extensive clinical trials to determine their genuine therapeutic potential in cancer treatment.

In conclusion, the extensive investigation of the PK, drug-likeness, and toxicological characteristics of anticancer flavonoids reveals a terrain rife with prospects and difficulties. This study deepens our understanding of these substances and opens the door to novel therapeutic approaches that use their unique qualities to advance cancer treatment.