Current Drug Metabolism - Volume 15, Issue 1, 2014

Anthocyanins are the largest group of water-soluble pigments in the plant kingdom. As with other polyphenols, they express antioxidant activity in vivo. Anthocyanins are associated with reduced risk of some several diseases, such as atherosclerosis and diabetes. Their beneficial health effects depend on the efficiency of their absorption. The intake of anthocyanins from the gastrointestinal lumen into the blood is likely to occur through the epithelium of the stomach, intestine and colon. The mechanisms of absorption differ from site to site, and they depend on the structure of the molecules that are absorbed. In plasma, anthocyanins can be found in their intact form, or as the corresponding phenolic acids and aldehydes, and also as methyl, sulfate and glucuronyl conjugates. Although aglycones can exist in plasma for short times, they are prone to degrade due to their instability; however, binding with proteins might preserve their intact structures. The plasma concentrations of anthocyanins are low, and efficient transport is crucial for their accessibility to tissues. Anthocyanins can cross the blood-brain barrier. However, besides their reduction of oxidative stress, the mechanisms behind their influence on neuronal activity are not completely understood. In this mini-review, we provide a short overview of the bioavailability, metabolic products, and transport processes of anthocyanins.

Green tea is one of the most popular beverages around the world. For several decades, numerous epidemiological, preclinical and clinical studies have demonstrated that green tea polyphenols (GTPs), especially epigallocatechin-3-gallate (EGCG) have cancer-preventing effects on various cancers. In this review, we present inhibition of carcinogenesis in different animal models by GTPs or EGCG, including prostate cancer, bladder cancer, breast cancer, intestinal cancer, colon cancer, gastric cancer, lung cancer, oral cancer and skin cancer. In vitro studies showed that GTPs/EGCG potently induces apoptosis, cell cycle arrest and suppresses metastasis in tumor cells but not in their normal cell counterparts. The molecular mechanisms of these activities are discussed in detail to elucidate GTPs/EGCG downstream carcinogenesis signaling pathways and their values of perspective of chemoprevention and treatment for cancers.

The development of food fortified with polyphenols and polyphenol-rich foods represents a novel approach to prevent or attenuate type 2 diabetes. It has been reported that type 2 diabetes may affect the pharmacokinetics of various drugs in several animal models. There is powerful evidence linking dietary polyphenols consumption with the risk factors defining type 2 diabetes, even if some opposite results occurred. This mini-review summarizes important advances on diabetes-associated changes in pharmacokinetics of natural polyphenols. The pharmacokinetic behavior between drugs and dietary polyphenols probably may be different due to (i) Ingested dose/amount per day. The dietary polyphenol intake per day is much higher than that of clinical drugs; (ii) Complexity of the components. Clinical drugs are well-characterized and typically small molecules. However, the polyphenols in diet are unimaginably complex; (iii) Interaction with food proteins. Although the effects of food proteins on the bioavailability of polyphenols are still not examined in much detail, direct binding interactions of polyphenols to proteins always occur; (iv) The most common polyphenols in the human diet have a low intrinsic activity and are poorly absorbed from the intestine, highly metabolized, or rapidly eliminated. Although there is very limited information available so far, it is proposed that type 2 diabetes influences the pharmacokinetic behavior of dietary polyphenols including: i) competition of glucose with polyphenols regarding binding to plasma proteins; ii) weakened non-covalent interaction affinities of plasma proteins for natural polyphenols due to protein glycation in type II diabetes; iii) the enhanced clearance of polyphenols in type 2 diabetes. An understanding of diabetes-associated changes in absorption, distribution, metabolism, elimination and bioactivities of natural polyphenols as well as the mechanism of the variability should lead to the improvement of the benefits of these polyphenols and clinical outcomes for diabetics.

Tea is an infusion of the leaves of the Camellia sinensis plant and is the most widely consumed beverage in the world after water. The main chemical components in teas are phenolic compounds (tea polyphenols, mainly tea catechins). A large number of in vitro and in vivo scientific studies have supported that the tea polyphenols can provide a number of health benefits such as, reducing the incidence of coronary heart disease, diabetes and cancer. Recently, tea polyphenols have proven highly attractive as lead compounds for drug discovery programs. A clear understanding of chemistry, stability, pharmacokinetics and metabolic fate of tea will be significant to elucidate many medicinal effects by biochemical theory and pharmaceutical development. This article reviews the current literature on the pharmacoknetics and biotransformation of tea catechins. The half-lives of tea polyphenols are 2-4h and their absorption and elimination are rapid in humans. The peak times (tmax) are 1 and 3 h after oral administration and the peak plasma concentrations are low μM range. It has been reported that catechins are easily metabolized by enzyme and microbe, and the main metabolic pathways are methylation, glucuronidation, sulfation, ring-fission metabolism, and so on. The information is important to discuss some of the challenges and benefits of pursuing this family of compounds for drug discovery.

At present, dietary polyphenols are popular with consumers because regular consumption of polyphenol-rich foods is likely to be beneficial for human health. However, administrated polyphenols are extensively metabolized in the digestive tract or some other parts before reaching the target organs. Additionally, some of the polyphenols are photosensitive, easily oxidized and are in unfavorable forms. Therefore, a lot of work has been performed to ensure delivery of intact polyphenols to the target organs. We here summarize recent progress in polyphenol-delivery to individual organs, tissues, and cells, in regard to relatively new delivery systems. Polyphenol-delivery systems can be divided into three categories: (i) before delivery into the blood stream (skin, mouth, gastrointestine), (ii) in the blood stream (plasma), and (iii) after the blood stream (brain, spleen, bone marrow, kidney). Polyphenols before the delivery into blood stream must overcome several obstacles to avoid converting into inactive forms by commensal microorganisms, environmental pH, and some others. In the blood, plasma-polyphenol interactions and modifications are very effective for the bioavailability of polyphenols with numerous enzymes. Native forms of polyphenols, successfully out of the blood stream, further go through obstacles such as the blood brain barrier to reach target organs. Recent progress in delivering polyphenols is here discussed on 3 main delivery systems, nanoparticle, liposome, and microemulsion. Moreover, we also focused on delivery systems to intracellular organelles (cell surface, lysosome, mitochondria, nucleus), which are the final targets of polyphenols to perform their beneficial reactions.

Flavonoids are naturally occurring polyphenols, which are widely taken in diets, supplements and herbal medicines. Epidemiological studies have shown a flavonoid-rich diet is associated with the decrease in incidence of a range of diseases. Pharmacological evidences also reveal flavonoids display anti-oxidant, anti-allergic, anti-cancer, anti-inflammatory, anti-microbial and anti-diarrheal activities. Therefore, it is critical to study the biotransformation and disposition of flavonoids in human. This review summarizes the major metabolism pathways of flavonoids in human. First, lactase-phlorizin hydrolase (LPH) and human intestinal microflora mediate the hydrolysis of flavonoid glycosides, which is recognized as the first and determinant step in the absorption of flavonoids. Second, phase II metabolic enzymes (UGTs, SULTs and COMT) dominate the metabolism of flavonoids in vivo. UGTs are the most major contributors, followed by SULTs and COMT. By contrast, phase I metabolism pathway mediated by CYPs only plays a minor role. Third, the coupling of transporters (such as BCRP and MRPs) and phase II enzymes (UGTs and SULTs) plays an important role in the disposition of flavonoids, especially in the enteroenteric and enterohepatic circulations. Thus, all the above factors should be taken into consideration when studying pharmacokinetics of flavonoids. Here we describe a comprehensive metabolism profile of flavonoids, which will enhance our understanding of the mechanisms underlying the disposition and pharmacological effects of flavonoids in vivo.

Several epidemiological studies throughout the years have suggested that polyphenols from fruits and vegetables promote health and reduce the risk of certain chronic and neurodegenerative diseases. Yet, it has been proved to be extremely difficult to quantitatively establish the benefit afforded by polyphenols, principally due to the limited understanding of the extent of its absorption and metabolic fate. Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an ingested polyphenol, its chemical changes in the body (e.g. by metabolic enzymes), and the effects and routes of excretion of the metabolites. In recent years, there have been major advances in our knowledge of polyphenol absorption and metabolism, and it is apparent that most classes of polyphenols are sufficiently absorbed to have the potential to exert biological effects. The pharmacokinetics of polyphenols includes the same steps as those for orally ingested drugs (LADME) and faces some of the same challenges, including transporters and enzymes. However, unraveling the bioavailability of polyphenols is even more challenging than with drugs, since many other factors, such as the variety in the chemical structure, the food matrix and the gut microbiota, can affect bioavailability of polyphenols during digestion. This review focuses on the most relevant factors that influence polyphenol pharmacokinetics, and also on the most recent technological strategies developed to overcome the poor bioavailability of phenolic compounds and thus increase their potential for greater health benefits.

The biochemical activities of plant flavonoids and stilbenoids point to many health-related applications, hampered however by a low bioavailability associated with rapid metabolic modification. A possible approach to overcome this obstacle is the development of prodrugs. In this review we provide some background information and summarize the efforts made so far to obtain suitable precursors of the two best known model polyphenols belonging to the classes just mentioned, quercetin and resveratrol. Prodrug design needs to take into account two key aspects: the nature of the chemical bond linking the core molecule to the protecting substituent, and the substituent itself, which can impart desirable physico-chemical properties. Only recently a systematic study of the several possible combinations has begun. Most bond systems tested so far appear to be either too stable or too unstable under physiological conditions. A range of substituent moieties is available, allowing the modulation of properties such as water solubility and the ability to permeate biomembranes. Work so far has been largely performed in vitro, and more in vivo experiments are definitely needed for a reliable assessment of the potentialities of the classes of prodrugs produced so far and of those still awaiting creation.

Significant advances have been achieved during the past decade concerning the metabolism of polyphenol compounds in vitro, but scarce data has been presented about what really happens in vivo. Many studies on polyphenols to date have focused on the bioactivity of one specific molecule in aglycone form, often at supraphysiological doses, whereas foods contain complex, often poorly characterized mixtures with multiple additive or interfering activities. Whereas most studies up to the middle-late 1990s measured total aglycones in plasma and urine, after chemical or enzymatic deconjugation, or both, several recent works now report the polyphenol conjugate composition of plasma, urine, feces and/or tissues, after the administration of pure polyphenols or polyphenol-rich matrices. HPLC methods with electrochemical, mass spectrometric and fluorescence detection have adequate sensitivity. LC/UV-Vis methods have also been widely reported, but they are much less sensitive. Compared with electro-chemical and fluorescence detection, MS can quantify analytes without chromatographic separation, which leads to high throughput, presenting itself as the best choice to date. Regarding the experimental model to monitor the bioavailability of phenolic compounds, most published studies are based on human and animal models, with the majority using rodents, primates and recently the nematode Caenorhabditis elegans. This review focuses on the fundamentals of pharmacokinetic methods from the last 15 years and how the results are evaluated and validated. The types of analytical methods, animal models and biological matrices were used to better elucidate pharmacokinetics of polyphenols.

Diabetes mellitus is one of the most serious diseases in the world. The degree of glycated plasma proteins is increased in diabetics compared to non-diabetic subjects. This mini-review focuses on the influence of glycation of human serum albumin (HSA) in diabetes on the binding interaction with dietary polyphenols. The non-enzymatic glycation of HSA leads to a conformational change in HSA, which in turn influences the ligand binding properties. HSA glycation is believed to reduce the binding affinities for acidic drugs such as dietary polyphenols and phenolic acids.

Flavonoids are natural polyphenols that can be found in many vegetables, citric fruits and dietary supplements and are widely consumed worldwide in the human diet. Over the past 30 years, studies have demonstrated that these compounds present significant biological activities, and their antioxidant properties may be responsible for the prevention of many diseases such as neurodegeneration, atherosclerosis, tumor generation, and microbial infections. Moreover, studies have shown that flavonoids may be substrates of cytochrome P450 enzymes and undergo bioactivation to metabolites that inhibit tumor cell growth. Therefore, it is important to understand the CYP450-mediated metabolic profiles of polyphenolic compounds during drug discovery and development processes. This review highlights ligand-based and structure-based methods to predict the Phase I metabolism of polyphenols. Moreover, an integrated in silico approach for the prediction of Phase I metabolism of the flavonoids quercetin, rutin, naringenin and naringin, which provided useful information about the most likely metabolites of these flavonoids and their interactions with amino acid residues of CYP2C9, is described.