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This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.Case Study 3. Application of Basic Enzyme Kinetics to Metabolism Studies: Real-Life Examples
An appreciation of the principles of enzyme kinetics can be applied in a number of drug metabolism applications. The concept for this chapter arose from a simple discussion on selecting appropriate time points to most efficiently assess metabolite profiles in a human Phase 1a clinical study (Subheading 4). By considering enzyme kinetics, a logical approach to the issue was derived. The dialog was an important learning opportunity for the participants in the discussion, and we have endeavored to capture this experience with other questions related to determination of K
m and V
max parameters,...
Source: Springer protocols feed by Pharmacology/Toxicology - February 14, 2014 Category: Drugs & Pharmacology Source Type: news
Case Study 4. Predicting the Drug Interaction Potential for Inhibition of CYP2C8 by Montelukast
Predicting Drug–Drug Interactions (DDIs) from in vitro data is made difficult by not knowing concentrations of substrate and inhibitor at the target site. For in vivo targets, this is understandable, since intracellular concentrations can differ from extracellular concentrations. More vexing is that the concentration of the drug at the target for some in vitro assays can also be unknown. This uncertainty has resulted in standard in vitro practices that cannot accurately predict human pharmacokinetics. This case study highlights the impact of drug distribution, both in vitro and in vivo, with the example of the drug i...
Source: Springer protocols feed by Pharmacology/Toxicology - February 14, 2014 Category: Drugs & Pharmacology Source Type: news
Case Study 5. Deconvoluting Hyperbilirubinemia: Differentiating Between Hepatotoxicity and Reversible Inhibition of UGT1A1, MRP2, or OATP1B1 in Drug Development
New molecular entities (NMEs) are evaluated using a rigorous set of in vitro and in vivo studies to assess their safety and suitability for testing in humans. Regulatory health authorities require that therapeutic and supratherapeutic doses be administered, by the intended route of administration, to two nonclinical species prior to human testing (ICH Expert Working Group. The international conference on harmonization of technical requirements for registration of pharmaceuticals for human use (ICH); Multidisciplinary guidelines; Nonclinical safety studies (M3).
http://www.ich.org/fileadmin/Public_Web_Sit...
Source: Springer protocols feed by Pharmacology/Toxicology - February 14, 2014 Category: Drugs & Pharmacology Source Type: news
Case Study 6. Transporter Case Studies: In Vitro Solutions for Translatable Outcomes
Assessing the interactions of a new drug candidate with transporters, either as a substrate or as an inhibitor, is no simple matter. There are many clinically relevant transporters, as many as nine to be evaluated for an FDA submission and up to eleven for the EMA as of 2013. Additionally, it is likely that if a compound is a substrate or inhibitor of one transporter, it will be so for other transporters as well. There are practically no specific substrates or inhibitors, presumably because the specificities of drug transporters are so broad and overlapping, and even fewer clinically relevant probes that can be used to eva...
Source: Springer protocols feed by Pharmacology/Toxicology - February 14, 2014 Category: Drugs & Pharmacology Source Type: news
Case Study 7. Compiled Aha Moments in Enzyme Kinetics: Authors’ Experiences
On 15 August 2012, USA Today reported that “aha moment” had been included in a list of new words being added to Merriam Webster’s Collegiate
®
Dictionary in the year 2012 (
http://content.usatoday.com/communities/entertainment/post/2012/08/oprah-has-a-moment-in-the-dictionary/1
; accessed on 25 August 2012 and
http://www.merriam-webster.com/info/newwords12.htm
; accessed on 25 August 2012). This word originated in the late 1930s, was popularized by modern day telev...
Source: Springer protocols feed by Pharmacology/Toxicology - February 14, 2014 Category: Drugs & Pharmacology Source Type: news
G Protein-Coupled Receptors: Research and Methods in the Post-Genomic Era
G protein-coupled receptors (GPCRs) are the number one class of receptor targets for the pharmacotherapy of many pathological and disease states. This chapter presents an overview of the chapter topics presented in this new volume on the genetics of GPCRs. (Source: Springer protocols feed by Pharmacology/Toxicology)
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
Examining the Dynamic Evolution of G Protein-Coupled Receptors
The valuable source of large-scale genomic information initiated attempts to identify the origin(s) of G protein-coupled receptors (GPCR), count and categorize those genes, and follow their evolutionary history. Being present in fungi, plants, and unicellular eukaryotes, GPCR must have evolved before the plant-fungi-animal split about 1.5 billion years ago. Phylogenetic analyses revealed several kinds of evolutionary patterns that occurred during GPCR evolution including one-to-one orthologous relationships, species-specific gene expansion, and episodic duplication of the entire GPCR repertoire in certain species lineages....
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
Functional Properties of Virus-Encoded and Virus-Regulated G Protein-Coupled Receptors
During coevolution with their hosts, viruses have developed several survival strategies that involve exploitation of 7 transmembrane spanning (7TM) G protein-coupled receptors (GPCRs). These include virus-encoded GPCRs and ligands and viral regulation of endogenous GPCRs. Many functional properties have been ascribed to virus-exploited GPCRs, and although the list of putative functions is steadily growing, the presence and/or function of virus-associated GPCRs is still poorly understood. This review focuses on three well-described functional properties of virus-associated GPCRs: (1) the immune evasion strategies, exemplifi...
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
Discovery and Function of the Very Large G Protein-Coupled Receptor
The very large G protein-coupled receptor 1 (VLGR1), also known as MASS1 or GPR98, is most notable among the family of adhesion GPCR for its size. Encoded by an 18.9 kb open reading frame, the ~700 kDa primary translation product is by far the largest GPCR and, additionally, the largest cell surface protein known to date. The large ectodomain of the protein contains several repeated motifs, including some 35 calcium binding, Calx-β repeats and seven copies of an epitempin repeat thought to be associated with the development of epilepsy. The extreme carboxyl-terminus contains a consensus PDZ ligand sequence, suggesting...
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
Functional Evolution of Opioid Family G Protein-Coupled Receptors
Opioid receptors are a family of receptors that belong to the type A GPCR group. Opioid receptors mediate a large myriad of physiological responses in different vertebrate species. There is evidence for the existence of opioid receptors from very early in evolution, and here we discuss a possible evolutionary path for their development. The physiological characteristics of the endogenous opioid system as well as the biochemical and pharmacological properties of these receptors are analyzed from an evolutionary viewpoint. Bioinformatic analysis from several groups supports the double whole-genome duplication (2R) theory, wh...
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
Investigation of G Protein-Coupled Receptor Function and Regulation Using Antisense
Delineation of GPCR function and regulation has relied heavily on the available pharmacological tools to manipulate GPCR activity, inhibit GPCR interacting proteins, or modulate downstream signaling molecules. Where appropriate agents are unobtainable, alternative molecular methods have been developed to determine the specific roles that individual proteins play in GPCR regulation and signaling. One such method utilizes RNA interference (RNAi) to suppress the expression of endogenous target proteins. The discovery that double-stranded (ds)RNA was able to deplete cellular protein expression paved the way for the development...
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
Signalosome Profiling Reveals Allosteric Interactions Between G Protein-Coupled Receptors
G protein-coupled receptors (GPCRs) comprise the largest group of cell surface receptors, translating environmental signals into cellular responses via cognate G protein partners. Contrary to our initial understanding, most GPCRs do not function in living cells as monomers, but most likely dimers, or even larger arrays of receptors. Standard drug design approaches rely on the notion that drugs binding the two receptors in a given dimer likely function independently of one another. However, this view has been challenged by recent work showing that ligand binding at both receptors can modulate dimeric receptors via allosteri...
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
Using In Vitro Mutagenesis to Characterize Structure-Function Relationships in G Protein-Coupled Receptors
The use of in vitro mutagenesis to characterize structure-function relationships in G protein-coupled receptors has led to the identification of specific amino acid residues that contribute to ligand binding, G protein coupling, and receptor folding. Mutagenesis is commonly used to change or mutate a DNA sequence so that one or more amino acid residues in a given G protein-coupled receptor are changed to different residues. These techniques can also be used to delete or insert one or more amino acids into a receptor and to exchange DNA sequences between homologous receptors. Of the available techniques, site-directed mutag...
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
The CRE Luc Mouse Model for Bioimaging Ligand Activation of G Protein-Coupled Receptors
Numerous assays have been developed to investigate the interactions between GPCRs and their ligands since GPCRs are key therapeutic targets. Reporter-based assays using the cAMP response element (CRE) coupled with bioluminescence from a luciferase reporter have been used extensively in vitro with high-throughput screens (HTS) of large chemical compound libraries. We have generated a transgenic mouse model (CRE luc) with a luciferase reporter under the control of a synthetic promoter that contains several CREs, which supports real-time bioimaging in whole animals, tissues, or primary cells of GPCR ligand activity. In the CR...
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
Inducing Conformational Changes in G Protein-Coupled Receptors by Domain Coupling
Our understanding of GPCR function has advanced considerably in the past few years primarily because advances were made in elucidating structures of several GPCRs and a new era of conformational dynamic studies of GPCRs is in fast progress. Traditional pharmacological studies in tissues and native cells yielded structure-function relationships through the manipulation of the drugs, resulting in a rich array of tools for research as well as use in therapeutics. Through the epoch of molecular cloning combined with analyses of structure-function of GPCRs, we learned the complexity of receptor subtypes, relationships within th...
Source: Springer protocols feed by Pharmacology/Toxicology - January 27, 2014 Category: Drugs & Pharmacology Source Type: news
