Current Drug Metabolism - Volume 16, Issue 3, 2015

Myeloperoxidase (MPO) is an important member of the haem peroxidase - cyclooxygenase superfamily. This enzyme is physiologically expressed in circulating neutrophils, monocytes and some tissue macrophages including microglia. MPO plays an essential role in the antimicrobial and antiviral system of humans. The microbicidal activity of MPO exists due to its capability to oxidize halide and pseudohalide ions (CI-, Br-, I- and SCN-) by H2O2, thereby producing respective hypohalous acids (HOX). During the phagocytosis of pathogens, azurophilic granules release their content together with MPO into phagolysosomes. On the other hand, MPO can be discharged outside the phagocytes. Due to this, tissue damage during inflammation is greatly promoted by MPO-derived oxidants. Regarding its activity, MPO is a key factor in a great number of conditions within the group of cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, kidney diseases and immune-mediated diseases. Therefore, MPO and its downstream inflammatory pathways might be attractive targets for both prognostic and therapeutic intervention in the prophylaxis of all mentioned illnesses. Nowadays, structure and reaction mechanism of MPO are known, which enable rational strategy in the development of specific MPO inhibitors that still preserve MPO activity during host defense from bacteria, but hinder pathophysiologically persistent activation of MPO. Various methods for MPO activity inhibition and unfavorable effects of MPO-derived oxidants remodeling will be discussed. Emphasis will be put on various known inhibitors, as well as on newly investigated natural products, which can also inhibit MPO activity.

Metabonomic studies quantitatively measure the small molecule metabolites and their intermediates in the biological samples (serum, urine or tissue extracts) and have gained wide applications in many fields, especially in toxicology. Pesticides are extensively used around the world and pesticide toxicity has become a serious threat to human health. Metabonomic approach has been applied in many aspects of pesticide toxicology research such as eco-environmental toxicity studies, biomarker identification, and mechanism of toxicity studies. Both whole organism animal models and cell culture models are used for metabonomic studies on pesticide toxicology. In the literature, metabonomic analyses on the toxicity of over thirty common pesticides, including insecticides, herbicides and fungicides, have been carried out using magnetic resonance spectroscopy or mass spectrometry. The combined toxicity of pesticides or pesticide with heavy metals was also investigated with metabonomic approach. In this article, recent progresses made in applying metabonomic approach in pesticide toxicology are thoroughly reviewed and the challenges with application of this approach are also discussed.

The application of lipid-based drug delivery systems on the industrial scale has successfully demonstrated their therapeutic and manufacturing advantages. Recently, various lipid-based formulations were successfully prepared for oral delivery of compounds that are difficult to administer. Nevertheless, an improved understanding of how these formulations affect drug absorption and metabolism is required to support the rapid and successful completion of drug development programs. In this review, we report the detailed mechanisms whereby lipids and lipid-based excipients affect drug absorption and metabolism, and summarize the capacity of lipids and lipid-based formulations to improve drug absorption by improving drug solubility, mucosa penetration, lymphatic transport, and hepatic metabolism. Finally, we discuss the progress made toward the use of novel lipid formulations to enhance oral absorption by surmounting specific absorption barriers.

Lipid emulsions have turned out to be a versatile tool for systemic delivery of poorly soluble drugs and cytotoxic drugs. Currently, the majority of marketed or developing drugs are recognized as BCS II and IV ones. How to solve the solubility and systemic administration that enables them access to clinical application is arising a great challenge in drug delivery systems. The key considerations for lipid emulsions are how to enhance the drug load, stability and reproducibility. Formulation and manufacture technique play the leading role in development of lipid emulsions. Understanding the biofate and characterization in vitro/vivo is suggestive to exploit the potential of lipid emulsions. This review discussed the manufacture techniques and in vivo behavior of lipid emulsions. Momentous interests were focused on their applications in drug delivery as well as the future evolution. Finally, we appreciated the methodologies of quality control and systemic risks associated with lipid emulsions.

While normal differentiated cells primarily use mitochondrial respiration to generate the required energy for cellular processes, most cancer cells rely on glycolysis, even in sufficient oxygen conditions. This phenomenon is known as the “Warburg effect” or aerobic glycolysis and the metabolic reprogramming of cancer cells towards this altered energy metabolism is currently recognized as one of the “hallmarks of cancer”. Aerobic glycolysis underlies the rapid growth of tumor cells, with high rates of glucose consumption and lactic acid production, leading to cellular acidosis. Metabolic reprogramming renders cancer cells dependent on specific metabolic enzymes or pathways that could be exploited in cancer therapy. The development of treatments that target tumor glucose metabolism is receiving renewed attention, with several drugs targeting metabolic pathways currently in clinical trials. The search for suitable targets, however, is limited by the high plasticity of the metabolic network that can induce compensatory routes. Deregulated glucose metabolism is a prominent feature associated with resistance to classical chemotherapy or oncogene-targeted therapies, strengthening the clinical potential of combining these therapies with glycolysis inhibitors. The aim of this review is to compare the advances of different therapeutic strategies targeting the glucose “addiction” of tumor cells, highlighting their potential as effective weapons against cancer. We further discuss recent evidence for the involvement of glucose metabolism as a compensatory response to the use of drugs that target different signaling pathways, where the combination with glycolysis inhibitors could prove extraordinarily useful.