A HANDBOOK OF BIOANALYSIS AND DRUG METABOLISM PDF

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A Handbook of Bioanalysis and Drug Metabolism. Front Cover. Gary Evans. CRC Press, Mar 29, – Medical – pages. A Handbook of Bioanalysis and Drug Metabolism is an invaluable guide to senior undergraduates and postgraduates studying drug metabolism in courses such. Download Citation on ResearchGate | On Nov 1, , Manfred E. Wolff and others published A Handbook of Bioanalysis and Drug Metabolism Edited by Gary.

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A Handbook of Bioanalysis and Drug Metabolism – Gary Evans – Google Books

Skip to main content. Log In Sign Up. Achieving these objectives is not easy, only a small percentage of the chemical compounds synthesised become medicines, most compounds prove unsuitable for reasons of efficacy, potency or toxicity.

Both the discovery and development phases are time-consuming processes which take between five and ten years to complete. When the potential drug is selected for development, extensive safety and clinical studies are conducted to provide sufficient data for a regulatory submission for registration of a new medicine. One group of scientists whose contribution is particularly important in both drug discovery and drug development are those working in the discipline which may be described as bioanalysis, pharmacokinetics and drug metabolism BPDM.

Whilst other names have been used to describe this discipline, it has broad range of activities which seek the same objectives — to understand what happens to the drug after it is administered metabolims to determine what implications a knowledge of the fate of the metabklism drug has for either improving the drug or for dosage regimens and safety.

Bioanalysis is a term generally used to describe the quantitative measurement of a compound drug in biological fluids primarily blood, plasma, serum, urine or tissue extracts. Pharmacokinetics is the technique used to analyse dtug data and to define a num- ber of parameters which describe the absorption, distribution, clearance including metabolism and w often referred by the acronym ADME. The ability to monitor the presence of the drug in the body and to measure its removal is critical in understanding the druv, dosage and efficacy metaabolism any medicine.

Drug metabolism is the study of the metabolism of a drug.

It can be used to discover the nature and route of metabolism of the drug and the information permits predictions to be made concerning the potential for interactions with co-administered drugs through knowledge of the enzymes involved in the metab- olism of drugs.

Increasingly predictions can be made about the metabolism of a putative drug using the knowledge base from drhg drugs. These three areas biianalysis developed together because of the use of common techniques and knowledge.

The scientists conducting these functions may be geographically separated or, increas- ingly, scientists may specialise in one of the functional areas. However, the functions are closely inter-related and may be considered a single scientific discipline. In this book this discipline will be referred to as BPDM.

Pf is used for decision-making in both phases; however, the nature of the decisions affects the quality and quantity of information required.

For discovery, the priority is to examine a large number of compounds and determine which pharmacologically active compounds are most suitable for drug development. In practice when a compound is obtained which has the required uandbook activity, a number of analogues or chemically similar compounds will be synthesised and tested to optimise the preferred characteristics of the compound a process is known as lead optimisation.

A Handbook of Bioanalysis and Drug Metabolism – CRC Press Book

In drug development, a single compound is progressed and information relating to the safety of the drug and the dosage required for efficacy in man is obtained.

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Consequently, the chapters in this book have been organised on the basis of functional topics and where there are different approaches for discovery and develop- ment these are discussed in each chapter. Physiochemical properties of compounds are also an important consideration in drug design as they will effect absorption and clearance.

They will also be of concern in the development of an analytical method or determining a suitable drug formulation. These aspects are discussed in detail in Chapter 2.

A Handbook of Bioanalysis and Drug Metabolism

A sensitive and specific bioanalytical method is developed to allow the monitoring of drug levels in plasma systemic circulating levels and urine excreted levels in clinical studies. The assay is also used to monitor the levels of exposure in pre-clinical safety studies. A bioanalytical method consists of two main components: The detector of choice is a mass spectrometer. These issues are discussed in Chapter 3 Sample preparationChapter 4 Chromato- graphic separation: The use of tandem mass spectrometry has reduced the need for extensive chromatographic separation because of the enhanced specificity and selectivity of this methodology.

It is especially valuable in lead optimisation for studying the pharmacokinetics of multiple compounds administered simultaneously.

In addition to monitoring the drug there is an increasing need with the advent of biochemically active com- pounds to monitor surrogate and biomarkers. These are endogenous compounds whose profile reflects the pharmacological action of the drug biomarker or disease surrogate. Immunoassay is the chosen technique for most endogenous compounds and surrogate markers. The use of immunoassay forms the subject of Chapter 6.

Plasma levels of the drug are normally monitored to permit the calculation of pharmacokinetic parameters. Whilst preliminary pharmacokinetic data is obtained in drug discovery in pre-clinical species, the definitive kinetics is obtained in drug development by conducting single dose experiments in pre-clinical species and in humans. The importance and definition of the pharmacokinetic parameters are discussed in detail in Chapter 7.

These data are essential in defining the dosage regimen in man and ensuring that the therapeutic benefit is maximised. Plasma samples are also taken from the pre-clinical species used in safety testing. In addition the calculation of total drug exposure in the safety studies is critical to calculating the margin of safety in clinical studies, and by scaling data from different species predictions can be made of the parameters in humans. All of these issues are discussed in Chapter 9.

The need to monitor both drug and biomarker levels is important for both discovery and development work. The priority for discovery is to ensure suitable pharmacokinetic properties of the chosen drug and to establish the relationship between systemic levels of drug pharmacokinetics, PK and the pharmacodynamics PD of the drug.

Pharmacological and toxicological effects are normally only produced by the free drug in the body. Most drugs are, to a greater or lesser degree, bound to proteins, notably serum albumen.

The techniques and importance of measuring protein binding are discussed in Chapter 10, illustrated with a case study on a highly protein-bound drug.

Many of the studies conducted in the development metaboljsm involve the use of radiolabelled drug which is not available at the earlier discovery phase. This allows the absorption, distribution, excretion and metabolism of the drug-related material to be investigated in the pre-clinical species, and where appropriate, in man.

These studies are essential in determining the elimination from the animal of all drug- related material. The excreta is used to examine the form of radioactivity and identify the metabolites. In addition, whole body autoradiography is used to follow the dis- tribution of radioactivity in the organs and the time period of elimination.

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This data is used quantitatively to determine the dose of radiolabelled drug which can be administered to human volunteers; however, these studies are becoming less com- mon as stable isotope alternatives are developed. All of these issues are ahndbook in Chapters 11 and The major routes of metabolism and the enzyme systems involved are well documented although it is an area under continuing development, particularly the Phase 2 enzyme systems.

Phase 1 metabolism Chapter 13 primarily consists of oxidation and hydrolysis of the parent molecule whilst conjugation is the main feature of Phase 2 metabolism Chapter In both instances the result is to render the molecule more polar and thus suitable for elimination from the animal. There are many in vitro techniques used to investigate the metabolism of compounds. The pros and cons of different models are discussed in Chapter These in vitro techniques allied to tools provided by molecular biological techniques Chapter 18 permit the scientist to identify the enzymes handbkok in the metabolism of a drug.

By considering the metabolism of co-administered drugs, predictions can be made about the potential for drug—drug interactions and reduce the need to conduct expensive clinical studies Chapter It is important to identify the metabolites and to show that the metabolites which were present in the pre-clinical species used in toxicity testing are the same as biosnalysis observed in humans.

Traditionally metabolite identification involved pains- taking extraction of radiolabelled drug from biological material and the use of spectrometric methods for identification. In recent years developments in nuclear magnetic resonance or NMR spectroscopy linked to chromatographic systems and mass boianalysis have revolutionised the ability to identify metabolites without extensive extraction, and from much smaller quantities of material. Examples of the use of these techniques are presented in Chapter Oof the pharmacologist or biochemist can develop a screening method for determining which compounds show biological activity against a particular target, these data are of limited value without the knowledge to determine whether the compound can be developed into a commercially viable medicine.

Indeed many homologous compounds may show similar biological activities in screens but may behave significantly differently when administered in vivo. The bioanalytical methods used in discovery are designed to be more generic and suitable to monitor a range of analogous compounds. The assay does not require the high sensitivity which is required in ddug development because the concentrations of compound used in the pharmacological screening models and initial in vivo testing are higher than will be encountered in the handnook studies.

Indeed only a small number of sampling times need to be taken to derive this information and many compounds may be co-administered bioanalysiss reduce the number of animals used in these studies.

The quality of information is of a level suitable for scientific evaluation and decision- making. The metabolism of putative drugs will be examined using in vitro screens. Bipanalysis vivo pharmacokinetics studies and in vitro metabolism studies are essential in explaining why some compounds active in vitro, in pharmacological models, show no or poor metaoblism vivo activity. The role of bioanalysis and drug metabolism in discovery is discussed in detail in Chapter Copyright by Gary Evans.

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