Human Drug Metabolism (eBook)

Michael D. Coleman (Autor)

eBook Download: EPUB

2019 | 3. Auflage
John Wiley & Sons (Verlag)
9781119458616 (ISBN)

Infos

Provides a timely update to a key textbook on human drug metabolism

The third edition of this comprehensive book covers basic concepts of teaching drug metabolism, starting from extreme clinical consequences to systems and mechanisms and toxicity. It provides an invaluable introduction to the core areas of pharmacology and examines recent progress and advances in this fast moving field and its clinical impact.

Human Drug Metabolism, 3rd Edition begins by covering basic concepts such as clearance and bioavailability, and looks at the evolution of biotransformation, and how drugs fit into this carefully managed biological environment. More information on how cytochrome P450s function and how they are modulated at the sub-cellular level is offered in this new edition. The book also introduces helpful concepts for those struggling with the relationship of pharmacology to physiology, as well as the inhibition of biotransformational activity. Recent advances in knowledge of a number of other metabolizing systems are covered, including glucuronidation and sulphation, along with the main drug transporters. Also, themes from the last edition are developed in an attempt to chart the progress of personalized medicine from concepts towards practical inclusion in routine therapeutics. The last chapter focuses on our understanding of how and why drugs injure us, both in predictable and unpredictable ways. Appendix A highlights some practical approaches employed in both drug metabolism research and drug discovery, whilst Appendix B outlines the metabolism of some drugs of abuse. Appendix C advises on formal examination preparation and Appendix D lists some substrates, inducers and inhibitors of the major human cytochrome P450s.

• Fully updated to reflect advances in the scientific field of drug metabolism and its clinical impact
• Reflects refinements in the author's teaching method, particularly with respect to helping students understand biological systems and how they operate
• Illustrates the growing relationship between drug metabolism and personalized medicine
• Includes recent developments in drug discovery, genomics, and stem cell technologies

Human Drug Metabolism, 3rd Edition is an excellent book for advanced undergraduate and graduate students in molecular biology, biochemistry, pharmacology, pharmacy, and toxicology. It will also appeal to professionals interested in an introduction to this field, or who want to learn more about these bench-to-bedside topics to apply it to their practice.

Michael D. Coleman, Presently Professor of Toxicology at Aston University. During his career, Dr. Coleman has studied and worked at Liverpool University, The Liverpool School of Tropical Medicine, Walter Reed Army Institute of Research in Washington D.C. and latterly Aston University. His substantial and original contribution to knowledge of the biochemical pharmacology and toxicology of antiparasitic drugs has been acknowledged in the award of the degree of Doctor of Science in 2005.

Textauszug

1
Introduction

1.1 Therapeutic window

1.1.1 Introduction

It has been said that if a drug has no side effects, then it is unlikely to work. Drug therapy labours under the fundamental problem that usually every single cell in the body has to be treated just to exert a beneficial effect on a small group of cells, perhaps in one tissue. Although drug‐targeting technology is improving rapidly, most of us who take an oral dose are still faced with the problem that the vast majority of our cells are being unnecessarily exposed to an agent that at best will have no effect, but at worst will exert many unwanted effects. Essentially, all drug treatment is really a compromise between positive and negative effects in the patient. The process of drug development weeds out agents that have seriously negative actions and usually releases onto the market drugs that may have a profile of side effects, but these are relatively minor within a set concentration range where the drug’s pharmacological action is most effective. This range, or therapeutic window, is rather variable, but it will give some indication of the most ‘efficient’ drug concentration. This effectively means the most beneficial pharmacodynamic effects for the minimum side effects.

The therapeutic window (Figure 1.1) may or may not correspond exactly to active tissue concentrations, but it is a useful guideline as to whether drug levels are within the appropriate range. Sometimes, a drug is given once only and it is necessary for drug levels to be within the therapeutic window for a relatively brief period, perhaps when paracetamol (acetaminophen) is taken as a mild analgesic. However, the majority of drugs require repeated dosing in time periods that range from a few days for a course of antibiotics, to many years for anti‐hypertensives and antithyroid drugs. During repeated intermediate and long‐term dosing, drug levels may move below or above the therapeutic window due to events such as patient illness, changes in diet, or co‐administration of other drugs. Below the lowest concentration of the window, it is likely that the drug will fail to work, as the pharmacodynamic effect will be too slight to be beneficial. If the drug concentration climbs above the therapeutic window, an intensification of the drug’s intended and unintended (off‐target) pharmacodynamic actions will occur. If drug levels continue to rise, significant adverse effects may ensue which can lead to distress, incapacitation or even death. To some extent, every patient has a unique therapeutic window for each drug they take, as there is such huge variation in our pharmacodynamic drug sensitivities. This book is concerned with what systems influence how long a drug stays in our bodies.

Figure 1.1 The therapeutic window, where drug concentrations should be maintained for adequate therapeutic effect, without either accumulation (drug toxicity) or disappearance (drug failure). Such is human variation that our personal therapeutic windows are effectively unique for every drug we take

Whether drug concentrations stay in the therapeutic window is obviously related to how quickly the agent enters the blood and tissues prior to its removal. When a drug is given intravenously, there is no barrier to entry, so drug input may be easily and quickly adjusted to correspond with the rate of removal within the therapeutic window. This is known as steady state, which is the main objective of therapeutics. The majority of drug use is by other routes such as oral or intramuscular rather than intravenous, so there will be a considerable time lag as the drug is absorbed from either the gastrointestinal tract (GIT) or the muscle, so achieving drug levels within the therapeutic window is a slower, more ‘hit and miss’ process. The result from repeated oral dosing is a rather crude peak/trough pulsing, or ‘sawtooth’ effect, which you can see in Figure 1.1. This should be adequate, provided that the peaks and troughs remain within the confines of the therapeutic window.

1.1.2 Therapeutic index

Drugs vary enormously in their toxicity and indeed, the word toxicity has a number of potential meanings. Broadly, it is usually accepted that toxicity equates with harm to the individual. However, ‘harm’ could describe a range of impacts to the individual from mild to severe, or reversible to irreversible, in any given time frame. There is a detailed discussion on what constitutes toxicity in Chapter 8 (sections 2 and 3), but for the meantime, the broad process of harm might begin with supra‐therapeutic ‘pharmacological’ reversible effects, progressing through to irreversible, damaging toxic effects with ascending dosage. Indeed, the concentrations at which one drug might cause potentially harmful or even lethal effects might be 10 to 1000 times lower than a much less toxic drug. A convenient measure for this is the therapeutic index (TI). This has been defined as the ratio between the lethal or toxic dose and the effective dose that shows the normal range of pharmacological effect.

In practice, a drug like lithium, for example, is listed as having a narrow TI if there is twofold or less difference between the lethal and effective doses, or a twofold difference in the minimum toxic and minimum effective concentrations. Back in the 1960s, many drugs in common use had narrow TIs, such as barbiturates, that could be toxic at relatively low levels. Since the 1970s, the drug industry has aimed to replace this type of drug with agents with much higher TIs. This is particularly noticeable in drugs used for depression. The risk of suicide is likely to be high in a condition that takes some time (often several weeks) to respond to therapy. Indeed, when tricyclic antidepressants (TCAs) were the main treatment option, these relatively narrow TI drugs could be used by the patient to end their lives. Fortunately, more modern drugs such as the SSRIs (selective serotonin reuptake inhibitors) have much higher TIs, so the risk of the patient using the drugs for a suicide attempt is greatly diminished. However, many drugs (including the TCAs to a limited extent) remain in use that have narrow or relatively narrow TIs (e.g. phenytoin, carbamazepine, valproate, warfarin). Therefore, the consequences of accumulation of these drugs are much worse and happen more quickly than drugs with wide TIs.

1.1.3 Changes in dosage

If the dosage exceeds the rate of the drug’s removal, then clearly drug levels will accumulate and depart from the therapeutic window towards potential harm to the patient. If the drug dosage is too low, levels will fall below the lowest threshold of the window and the drug will fail to work. If a patient continues to respond well at the same oral dose, then this is effectively the oral version of steady state. So, theoretically, the drug should remain in its therapeutic window at this ‘correct’ dosage for as long as therapy is necessary unless other factors change this situation.

1.1.4 Changes in rate of removal

The patient may continue to take the drug at the correct dosage, but at some point drug levels may drop out of, or alternatively exceed, the therapeutic window. This could be linked with redistribution of the drug between bodily areas such as plasma and a particular organ, or protein binding might fluctuate; however, provided dosage is unchanged, significant fluctuation in drug levels within the therapeutic window will be due to change in the rate of removal and/or inactivation of the drug by active bodily processes.

1.2 Consequences of drug concentration changes

If there are large changes in the rate of removal of a drug, then this can lead in extremis to severe problems in the outcome of the patient’s treatment: the first is drug failure, whilst the second is the drug causing harm (Figure 1.2). These extremes and indeed all drug effects are directly related to the blood concentrations of the agent in question.

1.2.1 Drug failure

Although it might take nearly a decade and huge sums of money to develop a drug that is highly effective in the vast majority of patients, the drug can only exert an effect if it reaches its intended target in sufficient concentration. Assuming that the patient has taken the drug, there may be many reasons why sufficient systemic concentrations cannot be reached. Drug absorption may have been poor, or it may have been bound to proteins or removed from the target cells so quickly it cannot work. This situation of drug ‘failure’ might occur after treatment has first appeared to be successful, where a patient was stabilized on a particular drug regimen, which then fails due to the addition of another drug or chemical to the regimen. The second drug or chemical causes the failure by accelerating the removal of the first from the patient’s system, so drug levels are then too low to be effective. The clinical consequences of drug failure can be serious for both for the patient and the community. In the treatment of epilepsy, the loss of effective control of the patient’s seizures could lead to injury to themselves or others. The failure of a contraceptive drug would lead to an unwanted pregnancy and the failure of an antipsychotic drug could mean hospitalization for a patient at the very least. For the community, when the clearance of an antibiotic or antiparasitic drug is accelerated, this causes drug levels to...

Produkt-Details

• Erscheint lt. Verlag: 23.12.2019
• Sprache: englisch
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Mikrobiologie / Immunologie
• Schlagworte: Biochemie • biochemistry • biotransforming • Biowissenschaften • Cell & Molecular Biology • Cell Biology • Chemie • Chemistry • Cytochrome P450 • Drug classes • drug inhibitors • Drugs • Drug toxicity • Genetik • genomics • human drug metabolism • Life Sciences • <p>drug metabolism • Metabolism • Molecular Biology • Molecular Pharmacology • Molekulare Pharmakologie • pharmacogenetics</p> • pharmacology • ‘Phase II’ conjugative • Toxicology • Zellbiologie • Zell- u. Molekularbiologie
• ISBN-13: 9781119458616 / 9781119458616