bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anatomical and Physiological Parameters that Influence Gastrointestinal Absorption
Authors: DeSesso John M. , Jacobson Catherine F. , Williams Amy Lavin 
Published: October 2012

AbstractThe rate at which ingested compounds are absorbed into the bloodstream from the gastrointestinal (GI) tract and extent to which they are absorbed are governed by the physical‐chemical properties of the ingested compounds, the presence and identity of other substances in the GI tract, and the anatomical and physiological characteristics of the GI tract. This chapter describes the anatomical and physiological similarities and differences between humans and some common laboratory animals, with an emphasis on the absorptive surface area of the GI tract, the time it takes for materials to move through the GI tract, and the nature of the GI contents.
General Principles of Drug Distribution
Authors: Wallace Gillian C. , Ramsden Diane B. , Grant M. Helen 
Published: October 2012

AbstractPharmacokinetics is the study of the fate of a drug in the body over time. In order to understand this process it is important to gain insight into the absorption, distribution, biotransformation (metabolism), and excretion (ADME) properties of a drug. This chapter will focus on the importance of understanding the general principles of drug distribution. Distribution describes the reversible transfer of drug within body compartments. This typically occurs via the bloodstream after entry into systemic circulation. Distribution of the drug to organs, muscle or tissue can reduce its apparent plasma concentration, and the extent to which a drug is distributed can be determined by calculating the volume of distribution (Vd). There are many factors that can impact how a drug is distributed throughout the body. These include both physiochemical (pKa, lipophilicity, ionization and molecular size) and physiological (rate of blood flow, and binding to serum proteins) factors. Another important determinant of drug distribution is the involvement of transporters. Transporters have been shown to be expressed in many types of tissues including barrier membranes. An understanding of the interaction between drugs and transporters can provide key insights into drug distribution, pharmacological effects and potentially non‐linear pharmacokinetics. This chapter will provide a good understanding of the key determinants of drug distribution as well as how data is obtained, interpreted and utilized to build a model with the objective of developing a more comprehensive understanding of a new chemical entity.
Mechanisms of Drug Metabolism
Authors: Foti Robert S. , Rock Dan A. , Wienkers Larry C. , Wahlstrom Jan L. 
Published: October 2012

AbstractThe study of drug metabolism places significant importance on the molecular properties of the substrate and the topography of the enzyme's active site. Mechanisms of drug metabolism focus on the different reactions catalyzed within each family of drug‐metabolizing enzymes as well as the chemistry involved in phase I and II reactions. Concepts explored include enzyme‐catalyzed reaction mechanisms, physicochemical properties of substrate molecules that result in favorable sites of metabolism for a given enzyme, and factors that contribute to the regioselectivity and stereoselectivity observed for phase I and II drug‐metabolizing enzymes.
Excretion Systems
Authors: Maeda Kazuya , Sugiyama Yuichi 
Published: October 2012

AbstractIn previous chapters, the expression and function of metabolic enzymes and drug transporters have been overviewed as important factors dominating ADME (the absorption, disposition, metabolism, and excretion) of drugs. As common features, each metabolic enzyme and transporter consists of a wide variety of isoforms, and the substrate specificity of each isoform is very broad, thereby providing an evolutionary ability to protect the body against numerous kinds of xenobiotics. Thus, a single compound can often be recognized by multiple metabolic enzymes and transporters as a substrate because it partly overlaps with different isoforms of enzymes and transporters. These molecules are appropriately located at several tissues in the body and increase efficiency in the detoxification of xenobiotics. For example, in the liver, efficient detoxification can be achieved by the sequential processing of compounds, such as in the cellular uptake from the blood circulation to hepatocytes via influx transporters, phase I and II metabolism, and biliary excretion via efflux transporters.In this chapter, we present an overview of how combinations of enzymes and transporters work concertedly as a detoxification “system”. Moreover, when evaluating the efficiency of detoxification quantitatively, because these molecules have different roles and do not function in parallel in this system, clearance of xenobiotics in each tissue cannot be expressed simply as the sum or product of an intrinsic clearance of each isoform of metabolic enzymes and transporters. Therefore, we will also discuss theoretical considerations and experimental methods to evaluate the influence of the function of each molecule on the overall efficiency of a detoxification system from the viewpoint of pharmacokinetics.
Pharmacokinetics and Toxicokinetics in Drug Discovery and Development
Authors: Varma Manthena V. S. , Radi Zaher A. , Rotter Charles J. , Litchfield John , El‐Kattan Ayman F. 
Published: October 2012

Abstract
Lack of efficacy and safety are considered to be the major contributing factors for drug failure in the clinic. Drug molecules with favorable pharmacokinetic profile are more borne to be both efficacious and safe. Therefore, inclusive preclinical pharmacokinetic assessment is a key to ensure compounds success in the clinic. This will be critical in weeding out weak clinical candidates early on. In addition, it is equally important to identify the probable causes of poor ADME exhibited by some compounds as this information is useful to medicinal chemists for improving upon backbones that exhibit un favorable pharmacokinetic profile.
Toxicity study is the foundation of an IND (Investigational new drug application) and therefore, the final selection of a compound can be performed only after proper toxicological evaluation in animal models. Toxicokinetics forms an integral part of toxicity study and is used to assess the exposure of candidates in toxicity models and correlate the drug levels in blood and various tissues with the toxicological findings. In this book chapter, an overview of the principles of drug pharmacokinetics and toxicokinetics is presented with introduction to the concepts of toxicogenomics and metabolites in safety testing.
Pharmacokinetic Data Analysis and Modeling ofADMEProcesses
Authors: Zhang Steven 
Published: October 2012

AbstractThe PK of unchanged drug and the pseudo‐PK parameters of total radioactivity (TRA) must be estimated in human ADME studies. With multiple PK samples collected in plasma and excreta, the PK parameters that represent the extent of a drug in or clearance from the circulation system are readily determined using a noncompartment approach that can be executed quickly in routine and traditional PK data analysis without assumption on disposition of drug in the body. Mechanism‐ or compartment‐based PK models contain specific expression to characterize, in a quantitative manner, processes on the causal path from absorption, distribution, and metabolism to elimination. Data analysis using modeling will provide information on not only the extent of a drug in the body but also the rate of a drug transferring through different parts of the body. Pooling PK data from a human ADME together with the data from the other studies of the same molecule can help scientists build a more robust population PK model, which can be used in interpreting or predicting the underlying physiological or pathological processes that drugs act on and for optimizing therapy with drugs that have a complex disposition.
Pharmacodynamics
Authors: Rao Indranil , Vinay HK , Mandlekar Sandhya 
Published: October 2012

AbstractPharmacodynamics is the science which deals with the physiological effects of drug on the body. A drug after reaching the blood circulation is transported to its target which may be a receptor or an enzyme which the drug agonizes or inhibits. This causes a response which can be measured and are known as biomarkers. Mathematical methods are then used to describe their temporal profile and further, to predict the effect at different doses, or help in design of further studies. This chapter deals with basic aspects of pharmacodynamics such as targets; types of actions; biomarkers; and a variety of mathematical models and methods.
Translational Drug Discovery Research: Integration of Medicinal Chemistry, Computational Modeling, Pharmacology,ADME, and Toxicology
Authors: Vangala Subrahmanyam , Pinjari Jakir , Patole Prashant , Ravindran Selvan , Gangal Rajeev , Wangikar Pralhad , Basu Sudipta , Ahmed Tausif , Rastogi Himanshu 
Published: October 2012

AbstractDiscovering a new drug is a complex but sequential process from discovery to preclinical development, followed with clinical drug development. It has been estimated that ∼ 87% of the phase III failures are accounted for either due to lack of efficacy (66%) or due to safety issues (21%). Majority of these failures are for compounds targeted for novel mechanisms of actions with unmet medical need, in particular, oncology and neurodegenerative disorders. Some of the reasons for these failures can be attributed to lack of appropriate preclinical animal models, biomarkers/surrogate markers, and effective pharmacokinetic (PK)–pharmacodynamic (PD) evaluation during early drug discovery. Translational research that integrates computer‐aided drug design (CADD), PK, PD, drug metabolism (DM), and drug transport along with biomarkers and humanized animal models are instrumental in making informed decisions from early drug discovery through clinical development. The ability to correlate drug effect through modeling and simulations starts from early drug discovery and preclinical evaluation, including use of novel biomarkers. Such models validate the PK and PD relationships and provide a basis for their applications and guide the Phase I through Phase III clinical trials more effectively, minimizing the late stage failures. Thus, PK–PD evaluation has become an integral part of drug discovery and provides valuable insights to aid in optimizing the next steps for drug development. This chapter is focused on translational drug discovery research with particular emphasis on selective utilization of CADD; absorption, distribution, metabolism, and excretion; toxicology; PK; and PD evaluations, which identify potential liabilities early so as to minimize late‐stage failures during drug development. This chapter also provides a brief overview on means and measures that can be adopted to integrate early drug discovery research along with efficacy and safety biomarkers for meaningful transition to drug development.
ADMEof Natural Toxins
Authors: González‐Pérez Vanessa , Kroll David J. 
Published: October 2012

AbstractA common myth among the general public is that any substance derived from nature is inherently safe. To the contrary, some of the most potent and specifically‐targeted toxins have been identified and isolated from plants, mushrooms, and microorganisms. With regard to this volume, many of these toxins are of particular relevance in the pharmacokinetic study of xenobiotics, particularly their metabolism. This chapter highlights a select group of primarily small molecule toxins or protoxins of historical (i.e., aflatoxins) or contemporary (i.e., mycotoxins from “toxic mold”) relevance. Marine peptide toxins are intentionally omitted to maintain focus but are an additional class of highly‐selective acute and potentially lethal toxins from nature.
Methods for Determination of Enzyme Kinetics and Metabolic Rates
Authors: Subramanian Murali , Tracy Timothy S. 
Published: October 2012

AbstractDetermination of the enzyme kinetics and clearance mechanisms of new chemical entities is critical in assessing their viability as new drug therapies. The first step in this process is choosing the appropriatein vitrosystem for these analyses. While liver microsomes are the most widely used system, they may not be the most appropriate if conjugative enzymes play a key role in the clearance pathways, where human hepatocytes may be more useful. Finally, expressed enzyme systems can provide some advantages in determining specific enzyme involvement. Overcoming the challenges of poorly metabolized compounds further complicates selection of the rightin vitrosystem. Once the appropriate biological test system has been identified enzyme kinetic parameters, includingVmaxandKm, can be determined. Optimally, determination of enzyme kinetic parameters is accomplished by measuring production of metabolite(s), but in cases where authentic standards of metabolites are not available, substrate depletion experiments may provide reasonable estimates. However, occasionally, atypical kinetics (non‐hyperbolic) may also be observed and appropriate kinetic models must be applied to assure thatin vitro–in vivocorrelations utilize the appropriateVmaxandKmvalues. In either case, typical or atypical kinetics, thein vitrokinetic parameters are subsequently scaled to predictin vivometabolic clearance, a critical step in making dose projections of the new chemical entity.
Utility of Molecular‐BasedIn VitroAssays in Metabolic Liability of Drug Candidates
Authors: Lee Ji Young , Moeller Timothy A. , Shipman Rob , Kaushansky Alexis , Sahi Jasminder 
Published: October 2012

AbstractMolecular‐based assays provide valuable information on the metabolic and toxicological liabilities of drug candidates afterin vitroandin vivotreatments. Pharmacogenetic and pharmacogenomic evaluations related to drug transport, metabolism, and safety have improved our understanding of the functional variability of genes involved in drug disposition. DNA and protein microarrays have helped to explain the effects of some genetic polymorphisms on drug disposition and idiosyncratic toxicities in subsets of populations. Nucleic‐acid‐based microarrays use DNA or mRNA fragments that hybridize specifically with complementary sequences and provide quantitative data on the effects of drug treatment on individual genes. Arrays can be customized to specifically understand ADME‐related changes in a limited number of genes or utilized to evaluate thousands of genes in order to form a more holistic picture of gene/protein changes after drug treatment as compared to parallel controls. Protein microarray technology is often used to complement the gene arrays and to study protein–ligand interactions. Microarrays are also used to study toxicogenomics, and the data are integrated to get an overall picture of the absorption, distribution, metabolism, excretion, and toxicology (ADMET) profile of a drug candidate. Thus, genomic and proteomic investigations coupled with computational analyses provide more predictive extrapolations of the ADMET profile of drug candidates.
In Vitro
Liver Systems to Study Induction/Inhibition: Prediction of
In Vivo
Metabolism and Drug–Drug Interactions
Authors: Komura Hiroshi , Iwaki Masahiro 
Published: October 2012

Abstract

This chapter was the review focused on the evaluation systems for metabolic stability, CYP inhibition and induction not only in the selection process of development candidates including lead optimizations in drug discovery but also to support a design of clinical studies in drug development. In the former process, the advanced
in vitro
systems have been developed, associating with an inevitable paradigm shift from the throughput to the quality. The similar trend has been gradually transmitted to the prediction of clearance and DDI. The predictions appeared to be in the movement from the basic models to the more mechanistic models including PBPK.
Precision‐Cut Tissue Slices: A SuitableIn VitroSystem for the Study of the Induction of Drug‐Metabolizing Enzyme Systems
Authors: Ioannides Costas , Lake Brian G. 
Published: October 2012

AbstractMost xenobiotic‐metabolising enzyme systems, and in particular the cytochromes P450, may be markedly up‐regulated following exposure to inducing agents. A rise in activity of these enzyme systems may lead to drug interactions with adverse or even fatal outcomes. Furthermore, modulation of these enzyme systems may bring about a profound change in an individual's susceptibility to a chemical toxin. The use of precision‐cut tissue slices as anin vitrosystem allows the rapid and facile investigation of the potential of a chemical to induce cytochrome P450 and other xenobiotic‐metabolising enzymes in different animal species, as well as in humans. Various tissues (e.g. liver, lung, intestine) can be used, and the effect of chemicals investigated in a concentration‐dependent manner, and employing a number of endpoints.
Integrated Approaches to Blood–Brain Barrier
Authors: Rong Haojing , Feng Bo , Di Li 
Published: October 2012

AbstractIn vivo, in vitroandin silicomethodologies are discussed to address the challenges of CNS drug discovery and development. The most important parameter that governsin vivopharmacology is the free drug concentration at the site of action in the brain. Four different approaches can be used to estimate free drug concentration in human brain. Lessons learned on prediction successes are highlighted using thirty‐two Pfizer clinical drug candidates with human CSF and/or receptor occupancy data.
Why Do We Need
In Vivo
Models in Drug Metabolism?
Authors: Beaumont Kevin 
Published: October 2012

Abstract

Despite the significant improvements in the use of
in silico
and
in vitro
models in drug metabolism, preclinical animal experiments are still required to fully understand drug disposition. Most drug discovery and development programs target human disease and so such
in vivo
experiments must be translatable to human. This is a problem since animals express different drug metabolizing enzymes and drug transporters and have different blood flow values to those in human. Consequently, pharmacokinetics and disposition can be very different between animals and humans. In general, passive processes (such as oral absorption, distribution of unbound drug and passive renal elimination scale well from animals to human. Scaling of active processes (such as metabolism and drug transport) can be prone to significant species differences, and require significant care in extrapolation to human. Due to gut physiology and species differences in metabolism, preclinical food effects and drug‐drug interaction studies are not recommended.
Utility of Genetically Modified Animal Models for Drug Metabolism and Drug Transporters
Authors: Bessire Andrew , Youdim Kuresh , Hurst Susan , Lee Caroline A. 
Published: October 2012

AbstractGenetically modified animals (GEMA) providein vivotools to understand the role of enzymes, transcriptional factors, and transporters in drug disposition and drug toxicities. Several phase I and II enzymes, transcriptional factors, and the clinically relevant drug transporters have been reviewed in this chapter by highlighting how the animal models have elucidated or validated their role in drug disposition, endogenous substrate regulation, or drug toxicities. The utility of animal models in research and drug development providesin vivotools to gain a better understanding of the role of drug‐metabolizing enzymes, transcriptional factors, and transporters in the absorption, disposition, metabolism, and drug‐related toxicities.
General Principles of Mass Spectrometry:GC‐MS,LC‐MS, andLC‐MS/MS
Authors: Thomas Brian F. , Daw Richard C. , Grabenauer Megan 
Published: October 2012

AbstractA variety of mass spectrometry techniques aid in both targeted and nontargeted analyses. This chapter introduces some of the most prevalent instrumentation for example, quadrupole, ion trap, and, time‐of‐flight mass spectrometers, as well as hybrid instrument configurations. Beyond the instrumentation itself, successful analytical techniques rely on a number of experimental design considerations including suitable ionization mechanisms, chromatographic approaches, and appropriate derivatization reactions. The most robust techniques applied toward structural elucidation, metabolite identification, or biomarker discovery involve high resolution accurate mass data, enabling isotope pattern analysis and mass defect filtering, as well an array of other data acquisition and processing techniques that capitalize on the enhanced mass accuracy. These advanced techniques are becoming more routine because of increases in computational power and advances in software tools to aid in data processing and interpretation.
A Perspective on the Evolving Field of Ambient Ionization Mass Spectrometry
Authors: Bereman Michael S. 
Published: October 2012

AbstractAmbient ionization mass spectrometry is a rapidly expanding field with applications ranging from biology, pharmaceuticals, polymers, environmental analysis to national security. These techniques perform ionization at atmospheric pressure with minimal sample preparation. The rate of introduction of these techniques has increased significantly over the last decade. In this chapter, methods are explained with schematics, and limitations of each method are discussed where applicable. Finally, several applications of these techniques are given using examples from the recent literature reports.
The Role of Biomarkers in Drug Discovery and Development: Enabling PK/PD
Authors: Szekely‐Klepser Gabriella , Kindt Erick 
Published: October 2012

AbstractThe goal of drug discovery and development is to find the right drug and to administer it at the right dose with the right frequency to the right patient. Biomarkers can be an invaluable tool to enable meeting this goal by confirming the efficacy and safety of drug candidates, providing an understanding of their mechanism of action, and determining the efficacious dose and dosing regimen by establishing the correlation between the pharmacokinetics (PK) and pharmacodynamics (PD) of the drugs. This chapter provides a definition of biomarkers and illustrates their roles and applications in pharmaceutical drug development.