bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzyme Kinetics of Drug‐Metabolizing Reactions and Drug–Drug Interactions
Authors: Kramer Melissa A. , Tracy Timothy S. 
Published: October 2012

AbstractIn vitrostudies play an important role in characterizing biotransformation reactions. Kinetic parameters are determined during the early phases of drug discovery and development and provide invaluable information needed to predictin vivometabolism and assess potential interactions with enzyme effectors. In order to obtain reliable and accuratein vitrodata that reflect thein vivosituation, one must employ well‐defined enzyme kinetic practices and reaction conditions. There are multiple factors to consider when conductingin vitrokinetic experiments such as enzyme concentration, addition of co‐substrates, buffering systems, and the effects that each of these may have on the experimental results. Of equal importance is to be aware of the potential caveats that may lead to erroneous results. An overview of the appropriate experimental conditions for kinetic studies is described, as well an explanation of which kinetic model is most appropriate when describing the kinetic results.Kinetic characterizations of most enzymatic reactions are governed by hyperbolic kinetics that can be described by the Michaelis–Menten equation. In some instances, atypical kinetic profiles have been observed. Atypical kinetics may result from multiple substrate molecules occupying the enzyme active site simultaneously. An overview of the fundamental concepts underlying both typical and atypical kinetic analysis is provided. In addition, the graphical representation and interpretation of the data is reviewed.In summary, the focus of this chapter is on general enzyme kinetic principles. These principles are presented in the context of defining drug metabolic clearance and drug inhibition potential. It is our hope to provide valuable insight into the complexities ofin vitrokinetics and the many challenges that surround quantitative prediction in drug metabolism.
Solute Carrier (SLC) Family Transporters
Authors: Sahi Jasminder , Lai Yurong , Lee Caroline 
Published: October 2012

AbstractXenobiotic transporters are required evaluated by the European and US regulatory agencies for the substrate and inhibition potential of drug candidates, due to the contribution of these to drug‐drug interactions. Interactions involving membrane transporters can alter the blood concentration time profiles of drugs, leading to altered levels of co‐administered drugs. Transporters play a role in toxicities, as inhibition of transporter activity could lead to increased drug concentrations or inhibition clearance of endogenous and exogenous substrates. While the SLC transporter family includes over 300 membrane bound transporters, less than 20 of these are currently considered relevant to drug related interactions. Of these, just eight are recommended by the regulatory agencies ‐ the ABC efflux transporters P‐gp and BCRP and the SLC uptake transporters OATP1B1, OATP1B3, OCT1 and BSEP which are hepatic, and the renal transporters OAT1, OAT3 and OCT2. This chapter discusses the major families of the SLC transporters that are involved in drug transport and provide information on structures, activities, substrates, inhibitors and genetic polymorphisms. Different in vitro and in vivo preclinical models are also discussed, so as to provide a more holistic view of these studies.
Mass Balance Studies in Animals and Humans
Authors: Lin Tsuhan , Heimbach Tycho , Gollen Rakesh , He Handan 
Published: October 2012

Abstract

Before first‐in‐human (FIH) studies with a new drug candidate, preclinical studies need to be conducted to fulfill regulatory requirements or to facilitate regulatory approval. In the United States, investigational new drug (IND) applications with the Food and Drug Administration (FDA) may include IND enabling studies, such as (i)
in vitro
and
in vivo
pharmacology studies for intended use, (ii) toxicology studies supporting the starting dose and duration of an FIH study (such as single‐ or multiple‐dose studies in one rodent and nonrodent species with toxicokinetics, genotoxicity battery, safety pharmacology battery), (iii) single‐dose pharmacokinetics (PKs) in one rodent and nonrodent species, (iv)
in vitro
plasma protein binding in relevant species, and (v)
in vitro
cross species metabolism study in relevant species. While not mandatory for IND submissions, comprehensive preclinical absorption, distribution, metabolism, and excretion (ADME) studies, including biotransformation or metabolite profiling, conventional mass balance, or tissue distribution by quantitative whole‐body autoradiography (QWBA) studies can make a submission package more compelling for progression toward phase I clinical studies. Typically, preclinical ADME together with mass balance studies are recommended before conducting human ADME and mass balance studies, which are generally initiated after the successful synthesis of the radiolabeled drug. For preclinical ADME species, the selection of doses is often based on pre‐existing toxicity information and targeted therapeutic doses. For human ADME studies, which include the evaluation of mass balance, a relevant dose in the anticipated therapeutic range is typically chosen. Conventional mass balance studies only allow the calculation of mass recovery and PK parameters of the radiolabeled drug by quantification of the radioactivity present in excreta such as urine, feces, or bile. Nowadays, these mass balance studies are often conducted as part of more comprehensive ADME studies, where additional information is obtained, including (i) PK properties of the drug and its metabolite(s) in blood or plasma; (ii) absorption estimates via plasma/blood data, urinary data, or fecal data; (iii) elimination pathways and drug metabolism; (iv) total drug exposure and its metabolites in different organs and tissues at different time intervals. In this chapter, fundamental scientific considerations for the successful design, conduct, and interpretation of conventional, basic mass balance and more comprehensive ADME studies are reviewed and discussed.
Role of
ADME
Studies in Selecting Drug Candidates: Dependence of
ADME
Parameters on Physicochemical Properties
Authors: Hop Cornelis E. C. A. 
Published: October 2012

Abstract

Drug discovery is a time‐consuming and expensive endeavor fraught with many glaring failures in clinical trials. Optimization of drug absorption, distribution, metabolism, and excretion (ADME) parameters continues to play an important role to ensure that the exposure is sufficient to achieve proof of concept, and ultimately efficacy, safely in clinical trials to address unmet medical need. This chapter provides an overview of various
in vitro
and
in vivo
ADME studies commonly employed in drug discovery. Emphasis will be placed on the dependence of ADME parameters on physicochemical properties. The literature has been reviewed to highlight key relationships. However, literature reviews mainly focus on retrospective analyses. Therefore, examples are included to illustrate how these principles can be embedded in drug discovery and used in a prospective drug design fashion with an emphasis on finding the physicochemical “sweet spot” that balances various properties.
In silico
(ADME) models should be an integral part of design as well and the value of various models has been illustrated.
Effective Early Drug Development
Authors: Bekersky Ihor , Walzer Mark , Reid Susan , Tolbert Dwain 
Published: October 2012

AbstractDrug development is a process that has no “short cuts” in spite of a detailed road map for developing safe and efficacious drugs. In this context, efficient drug development does not mean “quicker” or “less costly” but is a process that must maintain sight of safety and efficacy, produces information/data that is needed for “Go‐No Go” decisions using rational study designs and utilizes flexible study sequences‐not linear, ritualistic design. It is important to achieve the first goal: of an open IND, by use Exploratory Guidance as a tool to facilitate entry into humans when possible (IND‐enabling development). It should be kept in mind that phase 1/1a studies, whether in healthy subjects or patients, provides the learning phase of drug development, whereas, as development progresses to patients, the safe and effective use are confirmed and thus provide the basis for marketing approval.All aspects of drug development are not addressed here. The present report primarily addresses early development (phase 1)as in many cases the “Go‐NoGo” decisions are defined. An overview of the drug development process , regulatory aspects, and the important IND‐enabling development, is presented. Considering that all development begins with evaluations of animal safety/toxicity, specifics germain to the transition from animals to humans are presented in some detail. The importance of clinical pharmacology, pharmacokinetics, and biopharmaceutics receive a more in depth treatment; collectively as these are the pivotal “learning” areas for successful confirmation as development moves to patients. In this context, decision making studies such as proof of concept and several phase 1 scenarios are presented as examples, drug metabolism and drug–drug interactions studies (in vitroandin vivo) are discussed in some detail.As was stated earlier, an all‐encompassing review for drug development is not presented. However the text does provide a learning tool for those interested in the studies and decisions obtained to successful early drug development as a prelude to a more comprehensive development culminating with a safe and efficacious drug.
In SilicoModels of Drug Metabolism and Drug Interactions
Authors: Dimelow Richard J. , Metcalfe Paul D. , Thomas Simon 
Published: October 2012

AbstractIn silicomethods have multiple roles to play in drug discovery by reducing costs and increasing screening throughput compared toin vitroandin vivomethods, and by providing information to help guide chemical synthesis in producing compounds having desired properties. In terms of drug metabolism,in silicomethods can make predictions regarding the net rate of metabolism of a compound, the identity of enzyme isoforms that are likely to metabolise a compound, the concentration dependency of metabolism and the identity of expected metabolites. In terms of drug–drug interactions, models have been described for the inhibition of metabolism of one compound by another, and for the compound–dependent induction of drug–metabolising enzymes. Analogous models have been described for a number of properties of drug–transporting proteins. Physiologically‐based pharmacokinetic (PBPK) models can predict thein vivoconsequences of drug–drug interactions observed inin vitroassays or predicted byin silicomodels.In this chapter we discuss several areas in whichin silicomodeling can contribute to the quantitative or qualitative understanding and prediction of drug metabolism and drug–drug interactions. We describe a number of the availablein silicoapproaches to these application areas and discuss, in some detail, a number of specific application areas in which these methods have been used. We describe the use of physiologically based modelling to obtain predictions of the extent of drug–drug interactions expectedin vivo. We finish with a discussion of some practical aspects of applyingin silicomethods in drug discovery.
Monoclonal Antibody Analyses of Microsomal Human Drug Metabolism and Multifunctional Cytochrome P450
Authors: Krausz Kristopher W. , Gelboin Harry V. 
Published: October 2012

Abstract

Monoclonal antibody (MAb)‐based methods are ideal reagents for cytochrome P450 (P450) research. The properties and molecular diversity of P450s make them extraordinarily suitable for investigation with MAbs. The P450s are present in multiple forms. Defining the role of each P450 isoform for drug metabolism in human liver microsomes (HLM)
in vitro
requires a method that is both highly specific and highly inhibitory to P450 activity and thus can identify and quantitate the contribution of single or several P450 isoforms that metabolize the drug. MAbs have been isolated that are inhibitory and specific to 13 human P450s. The MAbs may also be used to determine the role of each P450 isoform for a variety of nondrug metabolizing activities such as mutagenesis carcinogen S9 activation and binding to DNA and others described in the text.
Introduction: An Overview of the Role of Metabolism in Drug Toxicity
Authors: Nelson Sidney D. 
Published: October 2012

AbstractThe scientific knowledge of drug‐mediated toxicities and the role that drug metabolites play in those toxicities has increased dramatically over the last 50 years. Advances in systems biology approaches to better define the most important factors in drug‐metabolism‐based toxicities should identify new biomarkers that can provide early signals of potential drug toxicities and lead to improvements in drug safety.
Covalent Drug–Protein Adducts: An Exploration of Their Role in Drug‐Induced Liver and General Organ Toxicity
Authors: Evans David C. 
Published: October 2012

AbstractOvercoming drug induced liver injury continues to represent a challenge for the pharmaceutical industry. Reducing metabolic drug bioactivation is a medicinal chemistry strategy that continues to represent the main platform to minimize this liability. Leveraging covalent binding studies to predict potential for liver toxicity has been widely investigated and appears to have some merit when performed in hepatocyte preparations and integrated with, for example, daily dose but clearly has limitations even when supplemented with data from additional assays that assess hepatotoxicity risk. Here we move beyond a discussion of acute liver toxicity as addressed by chemical synthetic strategies (focus on drug design) by exploring the underlying biochemical science and challenges that still exist regarding the predisposition of some people to idiosyncratic liver toxicity (focus on the individual). The hope is that the positive trajectory of the developing science in this area has the potential to deliver safer drugs to patients in need.
Drug–Drug Interactions 1: Inhibition
Authors: Subramanian Murali , Tracy Timothy S. 
Published: October 2012

AbstractPredicting a potential drug–drug interaction of a new drug is not only judicious but also mandatory given the high incidences of avoidable deleterious drug–drug interactions that increase the exposure of the victim drug in the subject's bloodstream. Typically, a new chemical entity is tested for its potency to cause a clinically relevant drug–drug interaction. This is determined inin vitrostudies that determine the mechanism of inhibition and the affinity of the inhibitor to a particular enzyme. The affinity (IC50orKi) is subsequently translated into a clinical AUC change viain vitro in vivocorrelations. Translational models have explored roles of fraction metabolized, protein binding, physiological inhibitor concentration, intestinal contribution and the role of non‐P450s towards worsening or ameliorating inhibition. Particular ambiguity exists in terms of the relevant concentration of inhibitor to be used in these models. While predictions have greatly improved and AUC changes within 2‐fold can be made at least 70–90% of the time, the presence of false negatives provides room for caution. Further refinement of the model includes incorporation ofin vivodata to build models, and building sophisticated compartmental models to improve prediction.
Hybrid Mass Analyzers in Drug Metabolism Applications
Authors: Chacko Silvi A. , Ramanathan Ragu , Griffith Humphreys W. , Josephs Jonathan L. 
Published: October 2012

AbstractAmong the analytical techniques used in the biopharmaceutical industry, liquid chromatography mass spectrometry (LC‐MS) assays are highly sought out by the drug metabolism and pharmacokinetic (DMPK) scientists due to their sensitivity, selectivity, specificity, and speed. Some of the desired qualities of the individual mass analyzers (quadrupole mass filters, ion traps and time‐of‐flights) and ion manipulation techniques are combined into one instrument to configure hybrid mass spectrometers. Such hybrid mass spectrometers become even more selective and specific when either time‐of‐flight or Fourier transform based high resolution mass spectrometers (HRMS) are combined with either ion traps or quadrupole mass filters. HRMS‐based hybrid mass analyzers, including quadrupole‐ time‐of‐flights, linear ion trap‐orbitrap, and quadrupole‐orbitrap, have begun to become front line mass spectrometers across the biopharmaceutical industry, especially in the DMPK laboratories. The focus of this book chapter is hybrid mass spectrometers based strategies and procedures available for detection and characterization of xenobiotics at various stages of drug discovery and development.
Micellar Electrokinetic Chromatography
Authors: Khaledi Morteza G. 
Published: October 2012

Abstract
Micellar electrokinetic chromatography (MEKC) has extended the scope of applications of capillary electrophoresis (CE) to separation of uncharged molecules. MEKC offers a combination of unique features of capillary zone electrophoresis (CZE) and reversed phase liquid chromatography (RPLC) such as high efficiency, rapid analysis, small sample size, and small solvent consumption. Another unique advantage of MEKC is the flexibility and versatility of incorporating chemical selectivity in the separation process through careful adjustment of the pseudo‐stationary phase composition. This chapter provides an overview of electrokinetic chromatography covering topics such as fundamental parameters influencing retention, selectivity, and resolution, an overview of different classes of pseudo‐stationary phases, detection, microfluidic platforms for MEKC separations, use of MEKC as part of two‐dimensional separation methods, and applications.
Plasma Protein Binding Methods in Drug Discovery and Development: Bioanalysis
Authors: Cohen Lucinda H. , Nicoll‐Griffith Deborah A. 
Published: October 2012

AbstractThis chapter provides an overview of both conventional and unconventional methods to determine plasma protein binding. Experiments using plasma protein binding advance our understanding of ADME properties to aid in drug candidate selection and development by determination of the unbound drug blood concentrations as well as (potentially) drug concentration at the site of action. Recent progress in automation as well as increased routine performance of the analytical instrumentation has enabled a greater number of compounds to be assayed earlier in discovery, and often with high enough quality to obviate the need for repeat studies during development. Significant effort has been invested to search for high throughput screening methods that reliably and accurately determine protein binding in early drug discovery. The development of 96‐well formats for equilibrium dialysis, ultrafiltration and ultracentrifugation, combined with liquid handling automation have transformed a formerly tedious, labor‐intensive assay into a process that can now be swiftly conducted. In addition, new approaches, referred to as emerging techniques, are also under investigation including chromatographic methods such as the human serum albumin column, spectroscopic methods including surface plasma resonance, solid phase microextraction, Transil™ membrane screening, and capillary electrophoresis methods. Several challenges still remain unsolved, particularly in cases of high protein binding with low exposure levels that fall below the normal limit of quantitation. This chapter describes the impact of high (>99%), undeterminable protein binding on compound developability as well as possible solutions including plasma dilution techniques.
DDI
Risk Assessment and Evaluation in Pharmaceutical Development: Interfacing Drug Metabolism and Clinical Pharmacology
Authors: Venkatakrishnan Karthik 
Published: October 2012

Abstract

Scientifically guided risk assessment and clinical pharmacologic evaluation of pharmacokinetic (PK) drug–drug interactions (DDI) are key components of contemporary drug development and play an integral role in the overall benefit/risk evaluation of new molecular entities (NMEs). DDI risk assessment and clinical evaluation should consider the potential for the NME to alter the PK of coadministered drugs (NME as the precipitant) and also the potential for coadministered drugs to alter NME PK (NME as the object). Risk assessment begins with
in vitro
and mechanistic studies of the NME's potential to alter drug disposition via inhibition or induction of drug‐metabolizing enzymes and transport proteins, and additionally, studies that elucidate the clearance mechanisms of the NME itself. This is followed by a mechanistic and quantitative translation of
in vitro
parameters to estimate clinical PK consequences of a potential DDI (i.e., expected increase in object drug exposure). When the risk for DDI cannot be definitively dismissed as low based on translational assessment from the results of
in vitro
studies, controlled clinical DDI studies are designed to evaluate the clinical pharmacologic correlates of the
in vitro
data. Finally, the results of clinical DDI studies will need to be interpreted in the context of knowledge of the therapeutic index of the object drug, gained from exposure–response understanding for both safety and efficacy endpoints. This chapter provides a technical overview and strategic perspectives on each of these aspects of DDI risk assessment and clinical evaluation, with the use of examples that illustrate applications in drug development and the translation of scientific knowledge to prescribing guidance, in the context of currently available regulatory guidance and published scientific opinion.