Current Drug Metabolism - Volume 20, Issue 14, 2019

Background: Phytochemicals are obtained from various plants and used for the treatment of diseases as both traditional and modern medicines. Poor bioavailability of phytochemicals is a major concern in applying phytochemicals as a therapeutic agent. It is, therefore, necessary to understand the metabolism and pharmacokinetics of phytochemicals for its implication as a therapeutic agent. Methods: Articles on the metabolism of phytochemicals from the PubMed database. The articles were classified into the digestion, absorption, metabolism, excretion, toxicity, and bioavailability of phytochemicals and the effect of gut microbiota on the metabolism of phytochemicals. Results: The metabolism of each phytochemical is largely dependent on the individual's digestive ability, membrane transporters, metabolizing enzymes and gut microbiota. Further, the form of the phytochemical and genetic make-up of the individual greatly influences the metabolism of phytochemicals. Conclusion: The metabolism of phytochemicals is mostly depended on the form of phytochemicals and individualspecific variations in the metabolism of phytochemicals. Understanding the metabolism and pharmacokinetics of phytochemicals might help in applying plant-based medicines for the treatment of various diseases.

Background: Pesticides are major xenobiotic compounds and environmental pollutants, which are able to alter drug-metabolizing enzyme as well as pharmacokinetics of drugs. Subsequent to the release of the human genome project, genetic variations (polymorphism) become an integral part of drug development due to their influence on disease susceptibility/ progression of the disease and their impact on drug absorption, distribution, metabolism of active metabolites and finally excretion of the drug. Genetic polymorphisms crucially regulate pharmacokinetics and pharmacodynamics of drugs under the influence of physiological condition, lifestyle, as well as pathological conditions collectively. Objective: To review all the evidence concerning the effect of environmental exposure on drug metabolism with reference to pharmacogenomics. Methods: Scientific data search and review of basic, epidemiological, pharmacogenomics and pharmacokinetics studies were undertaken to evaluate the influence of environmental contaminants on drug metabolism. Results: Various environmental contaminants like pesticides effectively alter drug metabolism at various levels under the influence of pharmacogenomics, which interferes with pharmacokinetics of drug metabolism. Genetic polymorphism of phase I and phase II xenobiotic-metabolizing enzymes remarkably alters disease susceptibility as well as the progression of disease under the influence of various environmental contaminants at various levels. Conclusion: Individual specific drug response may be attributed to a large variety of factors alone or in combination ranging from genetic variations (SNP, insertion, deletion, duplication etc.) to physiological setting (gender, age, body size, and ethnicity), environmental or lifestyle factors (radiation exposure, smoking, alcohol, nutrition, exposure to toxins, etc.); and pathological conditions (obesity, diabetes, liver and renal function).

Cancer is a complex disease that has the ability to develop resistance to traditional therapies. The current chemotherapeutic treatment has become increasingly sophisticated, yet it is not 100% effective against disseminated tumours. Anticancer drugs resistance is an intricate process that ascends from modifications in the drug targets suggesting the need for better targeted therapies in the therapeutic arsenal. Advances in the modern techniques such as DNA microarray, proteomics along with the development of newer targeted drug therapies might provide better strategies to overcome drug resistance. This drug resistance in tumours can be attributed to an individual’s genetic differences, especially in tumoral somatic cells but acquired drug resistance is due to different mechanisms, such as cell death inhibition (apoptosis suppression) altered expression of drug transporters, alteration in drug metabolism epigenetic and drug targets, enhancing DNA repair and gene amplification. This review also focusses on the epigenetic modifications and microRNAs, which induce drug resistance and contributes to the formation of tumour progenitor cells that are not destroyed by conventional cancer therapies. Lastly, this review highlights different means to prevent the formation of drug resistant tumours and provides future directions for better treatment of these resistant tumours.

Background: Conventionally, anti-cancer agents were administered through the intravenous route. The major drawbacks associated with the intravenous route of administration are: severe side effects, need of hospitalization, nursing care, and palliative treatment. In order to overcome the drawbacks associated with the intravenous route of administration, oral delivery of anti-cancer agents has gained tremendous interest among the scientific fraternity. Oral delivery of anti-cancer agents principally leads to a reduction in the overall cost of treatment, and aids in improving the quality of life of patients. Bioavailability of drugs and inter-subject variability are the major concerns with oral administration of anti-cancer agents. Factors viz. physicochemical and biological barriers (pre-systemic metabolism and transmembrane efflux of the drug) are accountable for hampering oral bioavailability of anti-cancer agents can be efficiently overcome by employing nanocarrier based drug delivery systems. Oral delivery of anticancer agents by employing these drug delivery systems will not only improve the quality of life of patients but will also provide pharmacoeconomic advantage and lead to a reduction in the overall cost of treatment of life-threatening disease like cancer. Objective: This article aims to familiarize the readers with some of the recent advancements in the field of nanobased drug delivery systems for oral delivery of anticancer agents. Conclusion: Advancement in the field of nanotechnology-based drug delivery systems has opened up gateways for the delivery of drugs that are difficult to administer orally. Oral delivery of anti-cancer agents by these drug delivery systems will not only improve the quality of life of patients but will also provide pharmacoeconomic advantage and lead to a reduction in the overall cost of treatment of life-threatening disease like cancer.

Background: Cancer cachexia is a metabolic syndrome prevalent in the majority of the advanced cancers and is associated with complications such as anorexia, early satiety, weakness, anaemia, and edema, thereby reducing performance and impairing quality of life. Skeletal muscle wasting is a characteristic feature of cancer-cachexia and mitochondria is responsible for regulating total protein turnover in skeletal muscle tissue. Methods: We carried out exhaustive search for cancer cachexia and role of mitochondria in the same in various databases. All the relevant articles were gathered and the pertinent information was extracted out and compiled which was further structured into different sub-sections. Results: Various findings on the mitochondrial alterations in connection to its disturbed normal physiology in various models of cancer-cachexia have been recently reported, suggesting a significant role of the organelle in the pathogenesis of the complications involved in the disorder. It has also been reported that reduced mitochondrial oxidative capacity is due to reduced mitochondrial biogenesis as well as altered balance between fusion and fission protein activities. Moreover, autophagy in mitochondria (termed as mitophagy) is reported to play an important role in cancer cachexia. Conclusion: The present review aims to put forth the changes occurring in mitochondria and hence explore possible targets which can be exploited in cancer-induced cachexia for treatment of such a debilitating condition.

Background: Sex and gender-based differences are observed well beyond the sex organs and affect several physiological and biochemical processes involved in the metabolism of drug molecules. It is essential to understand not only the sex and gender-based differences in the metabolism of the drug but also the molecular mechanisms involved in the regulation of drug metabolism for avoiding sex-related adverse effects of drugs in the human. Methods: The articles on the sex and gender-based differences in the metabolism of drug molecules were retrieved from the Pub Med database. The articles were classified into the metabolism of the drug molecule, gene expression regulation of drug-metabolizing enzymes, the effect of sex hormones on the metabolism of drug, expression of drugmetabolizing enzymes, etc. Results: Several drug molecules are known, which are metabolized differently in males and females. These differences in metabolism may be due to the genomic and non-genomic action of sex hormones. Several other drug molecules still require further evaluation at the molecular level regarding the sex and gender-based differences in their metabolism. Attention is also required at the effect of signaling cascades associated with the metabolism of drug molecules. Conclusion: Sex and gender-based differences in the metabolism of drugs exist at various levels and it may be due to the genomic and non-genomic action of sex hormones. Detailed understanding of the effect of sex and related condition on the metabolism of drug molecules will help clinicians to determine the effective therapeutic doses of drugs dependingon the condition of patient and disease.

Background: Nanoparticles (NPs) are being used extensively owing to their increased surface area, targeted delivery and enhanced retention. NPs have the potential to be used in many disease conditions. Despite widespread use, their toxicity and clinical safety still remain a major concern. Objective: The purpose of this study was to explore the metabolism and toxicological effects of nanotherapeutics. Methods: Comprehensive, time-bound literature search was done covering the period from 2010 till date. The primary focus was on the metabolism of NP including their adsorption, degradation, clearance, and bio-persistence. This review also focuses on updated investigations on NPs with respect to their toxic effects on various in vitro and in vivo experimental models. Results: Nanotechnology is a thriving field of biomedical research and an efficient drug delivery system. Further their applications are under investigation for diagnosis of disease and as medical devices. Conclusion: The toxicity of NPs is a major concern in the application of NPs as therapeutics. Studies addressing metabolism, side-effects and safety of NPs are desirable to gain maximum benefits of nanotherapeutics.