Current Drug Metabolism - Volume 16, Issue 7, 2015

The worldwide scientific community is in agreement that the activities of metabolic enzymes greatly impact the efficacies of anticancer drugs. Elucidation of the influences of these drugs on metabolism, especially that occurring in the liver, appears to be an extremely important step in the development of new anticancer drugs. Considering the continuous need to search for safe and effective chemotherapeutics, studies of the metabolism of new potent drugs are very important and should be included in the modern, innovative drug development pipeline. This article summarizes most of the current metabolic case studies involving anticancer drug development. Firstly, the impacts of diverse metabolic enzymes, particularly cytochrome P450, and the utilities of a few model in vitro enzymatic systems are described. Then, different analytical techniques, with particular emphasis on liquid chromatography- mass spectrometry detection and structural elucidation, are discussed. Finally, some computer-aided strategies for decisionmaking in the drug design process are described. Recent advances in drug development, including microdosing, in vitro-in vivo correlation and pharmacologic audit trail, are also discussed in relation to metabolic studies.

In recent years, multifaceted clinical benefits of polymeric therapeutics have been reported. Over the past decades, cancer has been one of the leading causes of mortality in the world. Many clinically approved chemotherapeutics encounter potential challenges against deadly cancer. Moreover, safety and efficacy of anticancer agents have been limited by undesirable pharmacokinetics and biodistribution. To address these limitations, various polymer drug conjugates are being studied and developed to improve the antitumor efficacy. Among other therapeutics, polymer therapeutics are well established platforms that circumvent anticancer therapeutics from enzymatic metabolism via direct conjugation to therapeutic molecules. Interestingly, polymer therapeutics meets an unmet need of small molecules. Further clinical study showed that polymer-drug conjugation can achieve desired pharmacokinetics and biodistribution properties of several anticancer drugs. The present retrospective review mainly enlightens the most recent preclinical and clinical studies include safety, stability, pharmacokinetic behavior and distribution of polymer therapeutics.

Adverse drug reactions (ADRs) are associated with clinical morbidity and, in severe cases, even mortality. Globally billions of dollars are spent on managing these ADRs for common and uncommon diseases. The developing world suffers from a high burden of tuberculosis, which requires 6-8 months of multi-drug treatment. In spite of most cases being treatable the problem persists mainly due to a high attrition rate associated with ADR mediated complications. Due to these reasons drug resistant strains have emerged and are now a serious challenge to TB eradication. To effectively deliver the available treatment regimen and ensure patient compliance it is important to manage ADRs more efficiently. Recent studies have demonstrated that drug outcomes are patient-specific and can, therefore be predicted. A few of these drugs, including a few administered for TB, have shown excellent correlation with response rates and development of ADRs. In this review, we profile information available in public domain for existing anti-TB drugs to understand the genesis of ADRs and patient response. Additionally, human genome variation databases have been used to correlate the frequency of these markers and their genomic variants in different populations.

Treatment regimen recommended for resistant tuberculosis consists of various drugs and these drugs are prescribed for at least 12-15 months. Such a long duration therapy and high dose of antibiotics result in adverse drug reactions (ADRs). ADRs may lead to various complications in disease management like replacement of drugs, dose increment, therapy withdrawal, etc. Linezolid is one of those drugs, practiced as an anti-mycobacterial agent and it is an important member of drug regimen for MDR and XDR tuberculosis. Linezolid is a broad spectrum antibiotic known for its unique mechanism of inhibition of resistant pathogenic strains. However, it causes serious adverse effects like thrombocytopenia, optic neuropathy, peripheral neuropathy, lactic acidosis, etc. Literature suggests that Linezolid can cause severe ADRs which affect patient compliance and hinder in therapy to a larger extent. Recent studies confirm the possibility of ADRs to be predicted with genetic make-up of individuals. To effectively deliver the available treatment regimen and ensure patient compliance, it is important to manage ADRs more efficiently. The role of pharmacogenomics in reducing adverse drug effects has been recently explored. In the present review, we discussed about Linezolid induced adverse drug reactions, mechanisms and genetic associations.

Glutathione (GSH), an abundant tripeptidyl molecule, plays pivotal roles in protecting cells against oxidative stress-induced cellular damage and in detoxifying xenobiotics and drug metabolism. GSH is now entering a new era of therapeutic applications. Decreased GSH levels are associated with the common features of aging as well as of a wide range of pathological conditions, including neurodegenerative disorders. Notably, GSH depletion and/or alterations in its metabolism appear to be crucial in the onset of Parkinson’s disease. Despite the fact that GSH is required for cell survival, the molecular mechanism that links GSH depletion to cell death remains poorly understood. Recently, considerable attention has been focused on a newly defined type of cell death: irondependent cell death, also referred to as “ferroptosis”. The iron chelator deferoxamine nearly abolishes ferroptosis induced by inhibiting GSH synthesis or cystine uptake by the xCT transporter. Deferoxamine preferentially abrogates the intralysosomal accumulation of iron and inhibits oxidative stress-induced lysosomal membrane permeabilization and cell death. The use of GSH and a prodrug derived from it can be useful, since the dysfunction of the GSH redox system appears to cause a variety of diseases including neurodegenerative disorders. However, the effectiveness of GSH as a therapeutic agent is limited because of its low bioavailability. We also review trials that have been designed to cope with this difficulty; e.g. the use of precursors such as N-acetyl cysteine and chemical modification such as methylation.

Subretinal neovascularization and pathologic ocular angiogenesis are common causes of progressive, irreversible impairment of central vision, and dramatically affect quality of life. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the quality of life for many patients with age-related macular degeneration, diabetic retinopathy, and other ocular diseases involving neovascularization and edema. In these pathologies, the inhibition of intraocular VEGF is the only therapy that can preserve vision. Four anti-VEGF drugs are currently used to treat ocular neovascularization; pegaptanib, ranibizumab, and aflibercept have been approved for this condition, while bevacizumab can be used off-label. Anti-VEGF therapy is administered regularly for many months or years because its suspension or discontinuation may cause recurrence of neovascularization. On the other hand, VEGF is necessary for the survival of retinal and choroidal endothelial cells. Experimental studies in animal models have shown that local inhibition of VEGF causes thinning and atrophy of the choriocapillaris and degeneration of photoreceptors, primarily cones. These studies combined with clinical experience indicated that prolonged VEGF inhibition could impair retinal function. Moreover, anti-VEGF compounds can cross the blood-retina barrier, enter the systemic circulation, and inhibit serum VEGF. Since circulating VEGF protects blood vessel integrity, prolonged anti-VEGF treatment could induce thromboembolic adverse events from vascular causes such as heart attack and stroke, and even death. The ocular dosing regimen and systemic toxicity of anti-VEGF compounds are therefore central concerns. A better understanding of this topic requires knowledge of the metabolism, tissue distribution, and clearance of anti-VEGF compounds. This manuscript reviews the properties of anti-VEGF compounds following intravitreal administration.

The rearrangements of the anaplastic lymphoma kinase (ALK) gene are key drivers in the carcinogenesis of a portion of anaplastic large cell lymphomas (ALCL) and non-small cell lung cancers (NSCLC). Crizotinib, an orally available small molecule, has been the first ALK inhibitor to demonstrate a significant clinical activity in patients with ALK-positive tumors and, thus, to achieve the US food and drug administration approval for the treatment of advanced NSCLC harboring ALK-rearrangements. However, despite initially dramatic and quite durable responses in most cases, acquired resistance to crizotinib arises unavoidably often within the first year of treatment. Three main mechanisms of resistance to crizotinib have been identified to date: mutations in the ALK kinase domain, amplifications of ALK gene, and activation of escape signaling pathways. As ALK signaling dependence is retained in most cases become refractory to crizotinib, newer and more potent ALK-inhibitors have been developed and tested in clinical trials with encouraging activity results. Ceritinib has been recently approved by FDA for the treatment of locally advanced and metastatic NSCLC, and several more agents, including alectinib, ASP3026, and X396, are in active clinical development, demonstrating to be safe, selective and potent. Dual inhibition approaches targeting both ALK and the escape pathways bypassing ALK are currently under investigation. Moreover, being ALK a partner of the heat shock protein Hsp90, inhibitors of this chaperone have been proposed as potential alternative therapeutic strategies for ALKdriven tumors.