Current Drug Metabolism (v.14, #7)
Pharmacogenetic Analysis of SNPs in Genes Involved in the Pharmacokinetics and Response to Lopinavir/Ritonavir Therapy by E. L (729-737).
Despite the known benefits and the experienced use of lopinavir/ritonavir (LPV/r) in the management of HIV infection, importantinterindividual variability in the pharmacokinetics (PKs) and the response to treatment with standard doses of this drug has been observed.Host genetic factors have been recently suggested as being responsible for part of this variability as they may affect the expressionand functional activity of many proteins involved in the kinetic behavior, the immune recovery or the adverse effects related toLPV/r.;Here, we present a genetic association study in 106 HIV-infected individuals collected over a period of 5 years with the aim of identifyingand confirming single nucleotide polymorphisms (SNPs) with a significant influence on the PK parameters of LPV/r, the immunovirologicalresponse or toxicity derived from treatment with the studied drug. Genotyping was performed by MALDI-TOF and KASPar;LPV/r plasma concentrations were quantified using high-performance liquid chromatography with an ultraviolet detection system and thePK parameters were estimated using Bayesian algorithms. Genetic association analysis was performed with SPSS.;The most significant associations were found between SNPs in the dopamine receptor D3 gene and the PK of LPV/r. Additionally, othersuggestive relationships were established between genetic factors and the response during treatment with this drug. Thereby, identifyingHIV-infected individuals who are at increased risk of achieve non-optimal LPV/r plasma concentrations with the emergence of toxicity,drug resistance or absence of clinical response could be helpful as a tool to optimize the LPV/r-based antiretroviral therapy.
Discovery of a Statistically Significant and Interpretable Relationship Between Redox Reactivity and Lethality of Drugs by Siu-Kwong Pang (738-744).
A statistically significant and interpretable relationship between electrophilicity as a redox reactivity indicator and LD50 as alethality indicator of drugs was discovered, and this relationship could be interpreted by the action of the cytochrome P450. The drugschosen in this study were Topoisomerase II inhibitor anticancer drugs, and the electrophilicity of drugs was obtained by quantum chemicalcalculation. Since the P450 detoxification mechanism is the catalytic oxidation of drug molecules, it may infer that the drug moleculesbeing easily oxidized (low electrophilicity) will be weak in lethality in general. In addition, this relationship revealed two structuralscaffolds for the anthracycline-based topoisomerase II inhibitors, and their lethality mechanisms are not totally the same. Such relationshipcan assist in designing new drugs that candidates possessing low electrophilicity are recommended for lowering of lethality, andmoieties providing a large inductive effect can reduce the electrophilicity of the anthracycline-based topoisomerase II inhibitors.
Combining In Silico Protein Stability Calculations with Structure-Function Relationships to Explore the Effect of Polymorphic Variation on Cytochrome P450 Drug Metabolism by Lauren Arendse, Tom L. Blundell, Jonathan Blackburn (745-763).
We carried out an in silico structural analysis of 348 non-synonymous single nucleotide polymorphisms, found across nine ofthe major human drug metabolising cytochrome P450 isoforms, to determine the effects of mutations on enzyme structure and function.Previous functional studies in our group have delineated regions of the cytochrome P450 structure important for substrate recognition,substrate and product access and egress from the active site and interaction with the cytochrome P450 reductase. Here we combine the informationfrom those studies with new in silico calculations on the effect of mutations on protein stability and we compare our results toexperimental data in order to establish the likely causes of altered drug metabolism observed for cytochrome P450 variants in functionalassays to date, in the process creating a cytochrome P450 polymorphic variant map.;Using the computational tool Site Directed Mutator we predicted destabilising mutations that result in altered enzyme function in vitrowith a specificity of 83%. We found that 75% of all cytochrome P450 mutations that show altered activity in vitro are either predicted tobe destabilising to protein structure or are found within regions predicted to be important for catalytic activity. Furthermore, we foundthat 70% of the mutations that showed similar activity to the wild-type enzyme in in vitro studies lie outside of functional regions importantfor catalytic activity and are predicted to have no effect on protein stability. Our resultant cytochrome P450 polymorphic variant mapshould therefore find utility in predicting the likely functional effect of uncharacterised variants on drug metabolism.
Neonatal Fc Receptor and its Role in the Absorption, Distribution, Metabolism and Excretion of Immunoglobulin G-Based Biotherapeutics by Craig Giragossian, Tracey Clark, Nicole Pich (764-790).
The neonatal Fc receptor (FcRn) is a heterodimeric membrane associated protein expressed in a variety of endothelial, epithelialand hematopoietic cells. FcRn regulates pH dependent intracellular trafficking of immunoglobulin G (IgG) and albumin, resulting inenhanced serum persistence and transcellular permeability of these proteins compared to other proteins of similar size. FcRn confers passiveimmunity during the early stages of life by facilitating maternal transmission of antibodies during gestation, and in some species duringthe neonatal period. The receptor continues to contribute to immunity beyond the perinatal period and throughout life by providingimmunosurveillance in intestinal, pulmonary and genitourinary mucosa. In this capacity, FcRn facilitates bidirectional transport of IgGacross mucosa and intracellular trafficking of antigen-antibody complexes in antigen presenting cells. Based on the functional roles ofFcRn in regulating serum persistence and transcellular permeability, protein engineers have sought to exploit this receptor as a means ofenhancing the absorption, distribution, metabolism and excretion (ADME) of IgG-based therapeutics. In this review, the current state ofknowledge regarding the structural, mechanistic and functional properties of FcRn, as they relate to the ADME of IgG-based therapeutics,are discussed.
Curcuminoid Metabolism and its Contribution to the Pharmacological Effects by Kun Wang, Feng Qiu (791-806).
Curcuminoids are safe natural yellow pigments used as food coloring agents and traditional drugs with a variety of biologicalfunctions such as antitumor, anti-inflammatory and antioxidant activities. Poor oral bioavailability and the low plasma concentration ofcurcuminoids limited their clinical use, and one of the major reasons is their rapid metabolism in vivo. The predominant metabolic pathwaysare reduction and conjugation, and some drug metabolizing enzymes such as alcohol dehydrogenase, UDP-glucuronosyltransferases(UGTs) or sulfotransferases (SULTs) involved in the metabolic reactions. Besides the major metabolic pathways, dehydroxylation, cyclizationand methylation can also occur in vivo. In addition, more than thirty metabolites of curcuminoids have been identified in biologicalmatrices including the plasma, urine and bile from rats or humans by LC-MS/MS analysis and other methods. Some metabolitessuch as tetrahydro-curcuminoids have been reported to be active, which may explain how and why curcuminoids with poor oral bioavailabilitydisplay their effectiveness in vivo. The present review mainly summarizes curcuminoid metabolism and its contribution to thepharmacological effects.
Capillary Electrophoresis?Mass Spectrometry in Metabolomics: The Potential for Driving Drug Discovery and Development by Xu Wang, Kefeng Li, Erwin Adams, Ann Van Schepdael (807-813).
Metabolomics represents the global profiling of metabolites in a given biological system. It has been used to facilitate pharmaceuticaldiscovery and development for over a decade. Advances in instrumentation have positioned capillary electrophoresis?mass spectrometry(CE-MS) as an important platform for both targeted and non-targeted metabolomics. In this mini-review covering the last fiveyears, we focus on the latest development of CE-MS based metabolomics in (a) identification and validation of novel valuable therapeutictargets, (b) evaluation of drug efficacy, and (c) monitoring of drug unanticipated adverse effects. Some of the current issues and futuredirections of CE-MS metabolomics are also discussed in the end.
Biological Insight, High-Throughput Datasets and the Nature of Neuro-Degenerative Disorders by Andr (814-818).
Life sciences are experiencing a historical shift towards a quantitative, data-rich regime. This transition has been associatedwith the advent of bio-informatics: mathematicians, physicists, computer scientists and statisticians are now commonplace in the field,working on the analysis of ever larger data-sets. An open question regarding what should drive scientific progress in this new era remains:will biological insight become increasingly irrelevant in a world of hypothesis-free, unbiased data analysis? This piece offers adifferent perspective, pin-pointing that biological thought is more-than-ever relevant in a data-rich setting. Some of the novel highthroughputinformation being acquired in the field of neuro-degenerative disorders is highlighted here. As but one example of how theoryand experiment can interact in this new reality, our efforts in developing an idiopathic neuro-degenerative disease hematopoietic stemcellageing theory are described.