Current Drug Metabolism (v.16, #1)

Meet Our Editorial Board Member: by Mª Jose Gomez-Lechon (1-1).

Preface: by Chandra Prakash (2-2).

Nucleic Acids Delivery Systems: A Challenge for Pharmaceutical Technologists by Ana C. Silva, Carla M. Lopes, Jose M. Sousa Lobo, M. Helena Amaral (3-16).
Nucleic acids (NA) therapies, including therapy with genes, aptamers or antisense oligonucleotides, have been showing promising results, especially in the treatment of severe diseases (e.g. cancer and AIDS). Nevertheless, the full success of medical treatments requires efficient achievement of the therapeutic target and also the safety and effectiveness of the pharmaceutical system. NA are not very efficient when administered alone, which means that the use of appropriate methods for in vivo transfection of these molecules into targeted cells is fundamental. Examples of these techniques are the use of viral and non-viral vectors to transfer the NA to the cells nucleus. Despite viral vectors have been demonstrating superior effectiveness for NA transfer, some drawbacks have been pointed out, which focused the research in the non-viral vectors. However, the development of effective NA delivery systems remains a challenge for pharmaceutical technologists, mainly because of their in vivo failure, which hinders their clinical application.
In this review article we address the characteristics of NA molecules and their respective limitations for formulation and administration. An update on the state of the art related to the latest and outstanding developments from the in vivo applications of NA viral and non-viral delivery systems is also presented. From this review, we can conclude that there is a lack of research regarding pre-clinical studies in specific animal models of disease, which is required for further human clinical trials and for their use in clinics.

Markers of Individual Drug Metabolism: Towards the Development of a Personalized Antidepressant Prescription by Celia Lloret-Linares, Frank Bellivier, Emmanuel Haffen, Jean-Michel Aubry, Youssef Daali, Kyle Heron, Patricia Berney, Jules Desmeules, Marie Besson (17-45).
The development of a personalized psychopharmacotherapy could potentially reduce treatment failure associated with drug intolerance or resistance, and therefore the burden and costs of affective disorders. An important challenge in realising this potential will be to identify suitable markers of an individual's metabolic response to specific pharmaceuticals.
In the absence of suitable markers related directly to drug mechanism, the drug-metabolizing enzymes and transporters have emerged as major determinants of variability in drug metabolism and response. In keeping with this emergent general pharmacological trend, numerous studies concerning the relationship between antidepressants, their metabolism, transport, pharmacokinetic properties, efficacy and tolerability have now been published. These studies are reviewed in this article.
The studies considered here frequently support a link between enzyme/transporter activity and/or the pharmacokinetic parameters of antidepressants. However, the majority of studies explored the variability of tricyclic antidepressants, which are less often prescribed today. Furthermore only a few studies have been conducted in naturalistic clinical conditions, seeking to determine whether the systematic assessment of the variability may improve the management of 'real-world' patients.
Nonetheless recent studies have yielded promising results regarding the potential benefits of determining drug metabolism variability which might encourage additional large-scale prospective systematic studies be set up to assess the relevance of this approach in everyday practice.

Systemic Redox Biomarkers in Neurodegenerative Diseases by Anna Pastore, Sara Petrillo, Emanuela Piermarini, Fiorella Piemonte (46-70).
Neurodegenerative diseases are characterized by a gradual and selective loss of neurons. ROS overload has been proved to occur early in this heterogeneous group of disorders, indicating oxidative stress as a primer factor underlying their pathogenesis. Given the importance of a better knowledge of the cause/effect of oxidative stress in the pathogenesis and evolution of neurodegeneration, recent efforts have been focused on the identification and determination of stable markers that may reflect systemic oxidative stress. This review provides an overview of these systemic redox biomarkers and their responsiveness to antioxidant therapies. Redox biomarkers can be classified as molecules that are modified by interactions with ROS in the microenvironment and antioxidant molecules that change in response to increased oxidative stress. DNA, lipids (including phospholipids), proteins and carbohydrates are examples of molecules that can be modified by excessive ROS in vivo. Some modifications have direct effects on molecule functions (e.g. to inhibit enzyme function), but others merely reflect the degree of oxidative stress in the local environment. Testing of redox biomarkers in neurodegenerative diseases has 3 important goals: 1) to confirm the presence or absence of systemic oxidative stress; 2) to identify possible underlying (and potentially reversible) causes of neurodegeneration; and 3) to estimate the severity of the disease and the risk of progression. Reflecting pathological processes occurring in the whole body, redox biomarkers may pinpoint novel therapeutic targets and lead to diagnose diseases before they are clinically evident.

With the rapid development of molecular biology, various of drug transporters have been discovered in several important organs of the body, which determine intracellular exposure and pharmacokinetic performances of drugs by modulating cellular entry and exit. This article focuses on the design of transporter-linked prodrug to enhance oral bioavailability and to acquire tissue-specific distribution pattern, especially paying attention to peptide transporter 1 (PepT1) and apical sodium dependent bile acid transporter (ASBT). Conjugation of the native promotety to active drug was one of the effective methods to improve membrane permeability and distribution profiles of drugs. In this review, we highlight the transporter-linked prodrug design modality based on PepT1 and ASBT. The biology of transporters, structure-transport relationship, key features of natural substrates and successful examples of transporter-linked prodrugs are overviewed in detail.