Current Drug Metabolism (v.16, #2)

Meet Our Editorial Board Member: by Kantharaj Ethirajulu (85-85).

CYPs are a large and diverse group of drug-metabolizing enzymes, which govern the metabolism of the majority of xenobiotic substances as well as endogenous components. The high inter-subject variability of CYP bioactivity has been largely attributed to gene polymorphism until the rapid development in epigenetics in the last decade that revealed another aspect of regulatory mechanism of drug-related genes. Epigenetics is the study of changes in gene expression or cellular phenotype that are not caused by changes in the underlying DNA sequence. The modification of histone proteins, together with DNA methylation and miRNAs, is the most extensively studied epigenetic mechanism in mammals. Recently, it has been demonstrated that alterations in epigenetic regulation occur during multiple pathological processes, especially carcinogenesis. As CYPs play an important role in carcinogen and anti-cancer drug biotransformation, epigenetic changes in CYP genes would lead to interindividual differences in drug responses. In this review, we provide an up-to-date summary of epigenetic studies on human CYPs, and discuss how such information could be integrated with clinical application.

Evidence-Based Choice of P2Y12 Inhibitors in End Stage Renal Disease Patients: A Mini-Review by Yassine Bouatou, Caroline Flora Samer, Pierre Fontana, Youssef Daali, Jules Desmeules (97-104).
Chronic kidney disease has been identified as an independent cardiovascular risk factor. The morbidity and mortality due to cardiovascular disease are higher among chronic kidney disease patients when compared with patients with normal kidney function. Although P2Y12 inhibitors (eg. clopidogrel) are associated with increased survival rates after a myocardial infarction, most of the clinical trials excluded End-Stage Renal Disease (ESRD) patients. Besides, non-responders to P2Y12 inhibitors have been identified as at risk of cardiovascular adverse events and non-responder prevalence is higher among ESRD than in any other population. Recent data questioned the benefits from P2Y12 inhibitors among chronic kidney disease patients. This systematic review aimed to describe pharmacokinetics (PK) and pharmacodynamics (PD) evidence data among 3 widely prescribed P2Y12 inhibitors. Clopidogrel and prasugrel are bioactivated by the cytochromes P450 (CYP) while ticagrelor is already active. PD data used different assays among which the VerifyNow® which showed intravariability before and after dialysis. The potential explanation of modulated PK/PD parameters among ESRD patients will be addressed. Absorption as well as metabolism is diminished in ESRD patients. It could potentially lead to absence of clopidogrel or prasugrel bioactivation or ticagrelor accumulation. Evidence-based recommendation regarding the best option for antiaggregation secondary to percutaneous intervention in this high risk population is still lacking.

The advent of highly active antiretroviral therapy has significantly reduced morbidity and mortality in human immunodeficiency virus (HIV) infection. Despite this reduction, complete eradication of HIV from the human body is not feasible in the nearly seen future. The central nervous system (CNS) is protected from blood-borne substances by a subtle structure of vascular endothelia known as blood-brain barrier (BBB). The BBB expresses transporters and metabolizing enzymes that modulate drug permeability in the CNS. This paper reviews the changes of the BBB phenotype as a physical and metabolic barrier in HIV infection. The effects of HIV and its proteins on intercellular junctions, influx and efflux transporters and metabolizing enzymes expressed at the BBB are reviewed. In HIV infection, the integrity of the BBB is severely compromised which often leads to serious neuropathological manifestations in the CNS. HIV and its proteins affect signaling pathways leading to oxidative stress, induction of matrix metalloproteinases and cytokines, down-regulation of different structural components of intercellular junctions, transporters and metabolizing enzymes. Taken together, HIV infection severely disrupts the integrity of the BBB and homeostasis of the CNS leading to modulation of drug disposition in the CNS and neurotoxicity. Applying knowledge of these mechanisms may lead to new therapeutic avenues to reduce neurological complications of HIV infection in the CNS.

Interaction of Isoflavones with the BCRP/ABCG2 Drug Transporter by Kristin M. Bircsak, Lauren M. Aleksunes (124-140).
This review will provide a comprehensive overview of the interactions between dietary isoflavones and the ATP-binding cassette (ABC) G2 efflux transporter, which is also named the breast cancer resistance protein (BCRP). Expressed in a variety of organs including the liver, kidneys, intestine, and placenta, BCRP mediates the disposition and excretion of numerous endogenous chemicals and xenobiotics. Isoflavones are a class of naturallyoccurring compounds that are found at high concentrations in commonly consumed foods and dietary supplements. A number of isoflavones, including genistein and daidzein and their metabolites, interact with BCRP as substrates, inhibitors, and/or modulators of gene expression. To date, a variety of model systems have been employed to study the ability of isoflavones to serve as substrates and inhibitors of BCRP; these include whole cells, inverted plasma membrane vesicles, in situ organ perfusion, as well as in vivo rodent and sheep models. Evidence suggests that BCRP plays a role in mediating the disposition of isoflavones and in particular, their conjugated forms. Furthermore, as inhibitors, these compounds may aid in reversing multidrug resistance and sensitizing cancer cells to chemotherapeutic drugs. This review will also highlight the consequences of altered BCRP expression and/or function on the pharmacokinetics and toxicity of chemicals following isoflavone exposure.

Novel Atypical Antipsychotics: Metabolism and Therapeutic Drug Monitoring (TDM) by Roberto Mandrioli, Michele Protti, Laura Mercolini (141-151).
Medicinal chemistry is continually developing and testing new drugs and drug candidates to satisfactorily address the needs of patients suffering from schizophrenia. In the last few years, some significant additions have been made to the list of widely available atypical antipsychotics. In particular, iloperidone, asenapine and lurasidone have been approved by the USA's Food and Drug Administration in 2009-10.
In this paper, the most notable metabolic characteristics of these new drugs are addressed, with particular attention to their potential for pharmacokinetic interactions, and to the respective advantages and disadvantages in this regard.
Moreover, current perspectives on the therapeutic drug monitoring (TDM) of the considered drugs are discussed. Since TDM is most valuable when it allows the personalisation and optimisation of therapeutic practices, it is even more interesting in the case of novel drugs, such as those discussed here, whose real impact in terms of side and toxic effects on very large populations is still unknown. Some analytical notes, related to TDM application, are included for each drug.

Polycation-Based Ternary Gene Delivery System by Shuai Liu, Tianying Guo (152-165).
Recent progress in gene therapy has opened the door for various human diseases. The greatest challenge that gene vectors still face is the ability to sufficiently deliver nucleic acid into target cells. To overcome various barriers, plenty of researches have been undertaken utilizing diverse strategies, among which a wide variety of polycation/pDNA vectors have been developed and explored frequently. For enhanced transfection efficiency, polycations are constantly utilized with covalent modifications, which however lead to reduced positive charge density and changed properties of polycation/pDNA complexes. Accordingly, non-covalent or ternary strategy is proposed. The cationic properties of polycations can be retained and the transfection efficiency can be enhanced by introducing additional polymers with functional groups via non-covalent assembly. This review will discuss the construction and advantages of ternary complexes gene delivery system, including low toxicity and enhanced gene expression both in vitro and in vivo. Recent progress and expectations with promising results that may have some reference for clinical application are also discussed.