Current Drug Metabolism - Volume 15, Issue 9, 2014

Flavonoids are important dietary phytochemicals with broad human exposures and a variety of claimed biological effects. Although traditional sources of flavonoids are fruits and vegetables, dietary supplements have become an important source of flavonoids. The enthusiasm for all things about flavonoids expressed by scientists and public alike has sometimes overlooked an important point: these compounds are usually not bioavailable or have very low bioavailability. The current review focused on factors that affect bioavailability of flavonoids, which in turn impact their efficacy and toxicity. These factors include physicochemical and biological ones, with the emphasis on the latter, including membrane permeation, enzymatic metabolism, and excretion by efflux transporters. Current evidence indicates that naturally occurring flavonoid glycosides typically need to be de-glycosylated before they are absorbed, because intact flavonoid glycosides are poorly absorbed. However, once absorbed, flavonoid aglycones undergo rapid and extensive first-pass metabolism via conjugation and subsequent excretion of the conjugates, which makes them poorly bioavailable. Fortunately, the presence of enteric and enterohepatic recycling allows the flavonoids to be accumulated in vivo over time, because the recycling increases contact time between the flavonoids and target tissues. We believe that continued studies in this area will help scientists devise a better means to improve oral bioavailability of flavonoids so we can one day fully enjoy the health benefits of ingesting flavonoids.

Drug metabolite identification and metabolic characteristics analysis play a crucial role in new drug research and development, because they can lead to varied efficacy, severe adverse reactions, and even toxicity. Classical methodologies for metabolite identification have mainly been based on mass spectrometry (MS) coupled with gas chromatography (GC) or liquid chromatography (LC), and some other techniques are used as complementary approaches, such as nuclear magnetic resonance (NMR). Over the past decade, more and more newly emerging techniques or technologies have been applied to metabolite identification, and are making the procedure easier and more robust, such as LC-NMR-MS, ion mobility MS, ambient ionization techniques, and imaging MS. A novel application of drug metabolite identification based on “omics” known as pharmacometabonomics is discussed, which is an interdisciplinary field that combines pre-dose metabolite profiling and chemometrics methods for data analysis and modeling, aiming to predict the responses of individuals to drugs.

Despite its undoubted benefit in patients with inflammatory bowel disease, anti-TNF therapy has some limitations including the lack of primary response and the loss of response to treatment in some patients. An empirical approach to these problems is frequently used based on clinical outcome. The measurement of anti-TNF drug serum levels and anti-drug antibodies (ADAb) levels has been proposed for improving the management of anti-TNF drugs. Although their role in routine clinical practice has not been clearly defined, current data support their relationship with clinical outcomes and suggest their clinical utility primarily in patients with loss of response to anti-TNF agents. The presence of pre-existing ADAb before starting the anti-TNF therapy has recently been described. Transient ADAb, non-neutralizing ADAb and some cut-offs points have been proposed, extending the knowledge about this topic. A standardized and widely available test with cut-off points for each anti-TNF agent and the definition of the most appropriate actions to be taken given the serum concentration of the drugs and ADAb are needed before recommending their routine use.

Nucleic Acid Based Drugs (NABDs) constitute a class of promising and powerful therapeutic new agents with limited side effects, potentially useable against a wide range of diseases, including cancer. Among them, the short interfering RNAs (siRNAs), represent very effective molecules. Despite their in vitro efficacy, the major drawback that limits siRNAs usage consists in a difficult delivery due to their very low stability in physiological fluids, and to their limited membrane-permeability through physiological barriers. On the other hand, the liposomes (lipid bilayers closed in vesicles of various sizes) represent interesting drug delivery systems (DDSs) which can be tailored in order to get the best performance in terms of load, vesicle size and transfection yield. In this work, the current state of study in these two fields, and the connections between them, are briefly summarized.

CYP1B1, a recently described dioxin inducible oxidoreductase, is a member of the cytochrome P450 superfamily involved in the metabolism of estradiol, retinol, benzo[a]pyrene, tamoxifen, melatonin, sterols etc. It plays important roles in numerous physiological processes and is expressed at mRNA level in many tissues and anatomical compartments. CYP1B1 has been implicated in scores of disorders. Analyses of the recent studies suggest that CYP1B1 can serve as a universal/ideal cancer marker and a candidate gene for predictive diagnosis. There is plethora of literature available about certain aspects of CYP1B1 that have not been interpreted, discussed and philosophized upon. The present analysis examines CYP1B1 as a peculiar gene with certain distinctive characteristics like the uniqueness in its chromosomal location, gene structure and organization, involvement in developmentally important disorders, tissue specific, not only expression, but splicing, potential as a universal cancer marker due to its involvement in key aspects of cellular metabolism, use in diagnosis and predictive diagnosis of various diseases and the importance and function of CYP1B1 mRNA in addition to the regular translation. Also CYP1B1 is very difficult to express in heterologous expression systems, thereby, halting its functional studies. Here we review and analyze these exceptional and startling characteristics of CYP1B1 with inputs from our own experiences in order to get a better insight into its molecular biology in health and disease. This may help to further understand the etiopathomechanistic aspects of CYP1B1 mediated diseases paving way for better research strategies and improved clinical management.