An Integrated Guide to Human Drug Metabolism: From Basic Chemical Transformations to Drug-Drug Interactions

By Mark Ashton, Paul W. Groundwater, Sophie Stocker and Adam Todd

An Integrated Guide to Human Drug Metabolism: From Basic Chemical Transformations to Drug-Drug Interactions uses the chemistry of each of the metabolic transformations to underpin the discussion of drug interactions with foods, herbal medicines and other drugs. Each of the human metabolic processes will be covered, employing examples drawn from known metabolic transformations of drugs used clinically. The clinical relevance of metabolism is discussed, focusing on appropriate prescribing (age-related dosage adjustments, routes of administration, and personalized medicines). Appropriate for use in the classroom or for self-study, An Integrated Guide to Human Drug Metabolism is useful for students and researchers needing a reference for interdisciplinary research in drug interactions.

Metabolism is at the center of personalized medicine, as it is a governing factor in the response of the patient to a drug. For example, does the patient express the genes, and so enzymes, which are responsible for the metabolism of a drug? Do they express the genes responsible for the bioactivation of a prodrug into its active form? Examples of clinically used agents for which metabolic phenotyping is essential will be used to highlight the increasing necessity for understanding the genetic profile of individual patients. This book includes questions and answers to gauge learning of each chapter, real-life case studies, and the basic science as a basis for the discussion of clinical aspects.

• Covers each of the human metabolic processes, employing examples drawn from known metabolic transformations of drugs used clinically
• Provides an integrated approach, linking together the science and practice strands of human drug metabolism
• Contains questions and answers to assess learning of material and real-life case studies

• Language: English
• Publisher: Academic Press
• Release date: May 13, 2024
• ISBN: 9780323993753

Mark Ashton

Dr Mark Ashton started his career in the pharmaceutical industry in 2002 working in both medicinal chemistry and process chemistry departments. In 2010, Mark joined the School of Pharmacy at Sunderland University as a Senior Lecturer in Medicinal Chemistry where he taught across a range of both undergraduate and postgraduate chemistry-based degree programmes, including all four stages of the MPharm degree. In 2017 Mark joined the School of Pharmacy at Newcastle University as a lecturer in Medicinal Chemistry where he has overseen the redevelopment of the chemistry strand of the MPharm degree to improve the integration between the science and practice aspects of the degree. His research interests include the development of new antiviral agents and synthetic biology.

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Introduction

Mark Ashtona; Paul W. Groundwaterb; Sophie Stockerb; Adam Todda, a School of Pharmacy, The Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom, b Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

Have you ever wondered why people taking certain medications are given advice not to eat certain foods? For example, people who are taking simvastatin to lower their cholesterol levels and thus help prevent cardiovascular disease should not drink grapefruit juice. Simvastatin is metabolized by cytochrome P450 3A4 (CYP3A4), a monooxygenase enzyme that is responsible for the metabolism of more than 50% of drugs. Grapefruit juice contains compounds that inhibit CYP3A4 and so prevent the metabolism of simvastatin, leading to an increase in the concentration of simvastatin in the blood and a greater potential for adverse effects.

Or why some drugs should not be given in combination with others? For example, if someone is taking warfarin to prevent the formation of blood clots, care should be taken when treating certain fungal infections, given that fluconazole, a commonly used oral antifungal agent, is an inhibitor of CYP2C9, a key enzyme in the metabolism of warfarin. In this case, an alternative antifungal that is not a CYP2C9 inhibitor should be prescribed, but the dose of warfarin could also be lowered while monitoring the time it takes for the patient’s blood to clot.

One of the major causes of drug-drug, drug-food, or drug-herb interactions is the effect of one drug on the metabolism of another. Pharmacokinetic studies, involving the absorption, distribution, metabolism, and excretion (ADME), are thus key components of drug discovery and development; an understanding of pharmacokinetics is also crucial to a range of topics, including how drugs are administered. For example, an understanding of first-pass metabolism helps us understand why nitroglycerin (glyceryl trinitrate), which is used in the treatment of angina, is administered sublingually, in order to rapidly achieve the required therapeutic concentrations. Human drug metabolism is thus an extremely important topic in many different taught courses related to health, as well as life sciences, and is also taught as a component of other courses, including pharmacology and medicinal chemistry.

What we have sought to do in this book is to use the chemistry of each of the important metabolic transformations and the enzymes responsible to underpin the discussion of the clinical relevance of metabolism. Each of the human metabolic processes is covered, employing important examples drawn from known metabolic transformations of drugs used clinically. Importantly, we have not included every example of a drug metabolized by a particular process but have tried to focus on important and illustrative examples.

Building upon these fundamental processes, we then discuss the clinical relevance of metabolism, focusing on appropriate prescribing (age-related dosage adjustments, routes of administration, and personalized medicines). Personalized (precision) medicine is an increasingly important area in which treatment is customized for an individual based upon their predicted response to a drug or their risk of disease. Metabolism is again at the center of this process as it is a governing factor in the response of the patient to a specific drug. For example, does a patient express the genes, and so enzymes, which are responsible for the metabolism of a drug? Do they express the genes responsible for the bioactivation of a prodrug into the active form? Examples of clinically used agents for which metabolic phenotyping is essential will be used to highlight the increasing necessity for understanding the genetic profile of individual patients.

We have enjoyed writing this book, and we have learned a lot from reading the many references we have included. We hope that you find the book equally as informative, whether you are using it as an introduction to human drug metabolism or as a means of finding a key reference relating to any of the biotransformations involved.

Throughout the text, images generated from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) (https://www.rcsb.org/) [1] are indicated by their PDB ID and publication citation. The images were generated from screenshots of the structure summary or by using Mol* [2].

Chemical structures were generated using ChemDraw Professional Version 22.2.0.3300.

Other images incorporate material licensed from Adobe Stock or Shutterstock.

We are hugely indebted to Prof. McLachlan for taking the time to read this book and for his very kind Foreword. Huge thanks also to the staff at Elsevier for their help and support and to Dr. Tom McDermott for his help with proofreading the text.

References

[1] Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., et al. The Protein Data Bank. Nucleic Acids Res. 2000;28(1):235–242.

[2] Sehnal D., Bittrich S., Deshpande M., Svobodová R., Berka K., Bazgier V., et al. Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res. 2021;49(W1):W431–W437.

Chapter 1 An introduction to pharmacokinetics and pharmacodynamics

Abstract

A knowledge of pharmacokinetics (what the body does to a drug) and pharmacodynamics (what the drug does to the body) is key to achieving the desired beneficial physiological effect resulting from a drug’s interaction with its target.

Safe medication administration is governed by the ‘5 rights’ of medication use:

• the right patient,

• the right drug,

• the right time,

• the right dose, and

• the right route of administration.

An understanding of how a drug is metabolized is crucial to deciding what dose is required, how best to administer it (and how often and how frequently), in order to optimize the success of therapy.

The metabolism of a drug can be crucial in terms of ending its pharmacological activity and eliminating it from the body, while for other drugs, metabolism is key to converting an inactive prodrug into its active form.

Keywords

Pharmacokinetics; Pharmacodynamics; Absorption; Distribution; Metabolism; Excretion

TLO: To gain an understanding of the different factors which contribute to pharmacokinetics and pharmacodynamics and an appreciation of the central role of metabolism.

The aim of any drug therapy is to achieve the desired physiological effect as a result of the drug’s interaction with its target. The science of pharmacology is the study of the properties and biological actions of drugs and encompasses pharmacokinetics and pharmacodynamics [1].

•Pharmacokinetics is the study of what the body does to a drug and describes the time course of a drug’s concentration in the body.

•Pharmacodynamics is the study of what the drug does to the body and describes the relationship between the drug concentration at the target and the drug response.

Sources of variability in the pharmacokinetics and pharmacodynamics of drugs are some of the reasons why responses to drugs are so variable and why individualization of drug dosing is required. The success of drug therapy relies upon our understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) processes that determine how well the prescribed drug therapy will achieve its desired effect. This chapter will describe key pharmacokinetic and pharmacodynamic principles to help you understand how they apply to an individual patient. Understanding these concepts provides the means of prescribing the right dose for that individual patient, thereby optimizing the therapeutic effect and minimizing the adverse effects. This involves achieving a plasma concentration (drug exposure) within the ‘therapeutic window’, which is above the minimal effective concentration but below the minimal toxic concentration.

1.1 Pharmacokinetics

ELO: Gain an understanding of what the body does to a drug and ADME (in particular the role of metabolism)

The sites at which drugs are commonly administered can be broadly classified as intravascular or extravascular, Fig. 1.1.1. Intravascular drug administration refers to drug administration directly into the blood (e.g. intravenously or intra-arterially). Extravascular drug administration includes buccal (between the cheek and the gums), sublingual (under the tongue), intradermal, intramuscular, oral, pulmonary (inhalation), subcutaneous (into fat under the skin), rectal and vaginal. If a drug is administered via an extravascular route, an additional step, absorption, is required for the drug to reach the systemic circulation in comparison to intravascular administration.

Fig. 1.1.1

Fig. 1.1.1 Some of the most common routes of drug administration.

Once it has reached the systemic circulation, a drug is distributed to the various organs of the body by the blood. Drugs are eliminated from the body mainly via excretion of unchanged drug (via the kidneys) or metabolism (via the liver) with these metabolites being excreted (or further metabolized). These processes of drug Absorption, Distribution, Metabolism and Excretion, often referred to as ADME, encompass drug pharmacokinetics [1,2]. The fate of a drug in the body following its administration can be described by hypothetical mathematical models, including one or multi-compartment models.

One compartment model

In this simple model the body is considered as a single container (one compartment) in which the drug is instantly and uniformly distributed throughout the body, Fig. 1.1.2. In this instance the drug concentration-time profile shows a monophasic (mono-exponential) response. It is important to note that the concentration of a drug in plasma is not necessarily the same as in other tissues (e.g. liver, kidney) so the one compartment model is an over simplification.

Fig. 1.1.2

Fig. 1.1.2 Schematics of the models used to describe drug distribution in the body; (A) the one-compartment model and (B) a two-compartment model.

Two compartment model

Slightly more complex is the two-compartment model, which includes a central compartment and a peripheral compartment. Although these compartments have no physiological meaning, it is generally assumed that the central compartment comprises highly perfused tissues such as the heart, lungs, kidneys, liver and brain. In contrast the peripheral compartment comprises less well-perfused tissues such as muscle, fat, bone and skin. A two-compartment model assumes that after drug administration, the drug distributes between the central and peripheral compartments. However, unlike with the one compartment model, this distribution is not instantaneous, i.e. it takes some time for the drug to arrive in the peripheral compartment. The drug concentration-time profiles show a biphasic (multi-exponential) response, Fig. 1.1.2. There is an initial rapid decline in concentration, owing to the rapid elimination of drug from the central compartment as it moves into the peripheral compartment. Some drugs, such as gentamicin, are best described by a 3-compartment model.

The rate of change of drug concentration over time (i.e. how quickly the drug is absorbed, distributed, metabolized, eliminated) can be described as either zero-order or first-order.

Zero-order describes the situation when the amount of a drug is eliminated from the body at a constant rate, Fig. 1.1.3; that is, plasma concentrations decline linearly with time. An example is alcohol (ethanol), for which concentrations decline at a constant rate of approximately 15 mg/100 mL/h. The rate of decline is independent of the concentration of the drug in the body. Drugs that exhibit zero order kinetics have non-linear pharmacokinetics.

Fig. 1.1.3

Fig. 1.1.3 The rate of change of drug concentration over time for a drug which exhibits zero order kinetics (brown) or first order kinetics (blue).

The more common situation is first order elimination, where the decline in drug concentrations varies over time, Fig. 1.1.3. The rate of decline is proportional to (dependent upon) the concentration so, for drugs that exhibit first order kinetics, if you double the dose you will double the concentration. However, if you continue to increase the dose (e.g. in an overdose situation), at some point the drug will change from exhibiting first order kinetics to zero order kinetics.

Most drugs are administered continuously over a period of time. When a drug is administered regularly it will accumulate in the body and the plasma concentrations will rise until steady-state conditions have been achieved. Steady-state occurs when the amount of drug administered (over time) is equal to the amount of drug eliminated over the same time period. The time to reach steady-state is dependent on the drug’s half-life (t1/2) and it takes approximately 5 half-lives to achieve steady-state and this is not dependent on the dose.

For example, consider a drug with a half-life (t1/2) of 3 h; dosing every 2 h (dosing interval < half-life) will lead to accumulation of the drug. If the drug is dosed every 10 h (dosing interval > half-life) there will be no accumulation, and the concentration-time profile will reflect the administration of a series of single doses.

We will now look briefly at the components of ADME, before focusing on the topic for this book, human drug metabolism which, you will see, affects both the bioavailability and clearance of a drug.

1.1.1 Drug absorption

Absorption is the process by which an unchanged drug moves from the site of administration to the site of measurement in the body (usually plasma obtained via venipuncture). Absorption is usually a passive process that is governed by the principle of diffusion (i.e. a flow from high to low down a concentration gradient). The absorption of small drug molecules involves movement across a biological membrane and into blood cells and there are several mechanisms by which drugs can achieve this: diffusion (passive and facilitated), active transport, and endocytosis (for very large molecules).

Most drugs cross cell membranes by passive diffusion, in which the drug must pass from an aqueous phase, through a hydrophobic membrane (phospholipid bilayer), back into an aqueous phase, Fig. 1.1.4. This process is thus governed by the partition coefficient of the drug,a and drugs with no ionizable functional groups will most easily traverse biological membranes. As the drug must be in its neutral form to traverse the lipid (hydrophobic) portion of the membrane, Fig. 1.1.5, we might expect that acidic drugs would be best absorbed in the stomach (pH 1–3; where they are most neutral), while basic drugs would be best absorbed in the small intestine (pH ∼7; where there is the highest proportion of their unionized form).b In actual fact, the stomach has a much smaller surface area (due to the presence of villi in the small intestine), drug residence time, and blood supply than the small intestine, so most drug absorption occurs in the small intestine.

Fig. 1.1.4

Fig. 1.1.4 (A) Passive diffusion of a hydrophilic, water-soluble drug through an aqueous channel or pore or a hydrophobic drug (lipid soluble) through a membrane; (B) facilitated drug diffusion through a drug transporter; (C) active drug transport through a drug transporter.

Fig. 1.1.5Fig. 1.1.5

Fig. 1.1.5 Passive diffusion of (A) diclofenac (an acid, p K a 4.15) and (B) clopidogrel (a base, p K a 5.3) from the small intestine (pH 7) to blood (pH 7.4).

Bioavailability (F) is the fraction of the dose (expressed as a %) of drug given that reaches the systemic circulation. For a drug that is administered intravenously, F is equal to 100%, i.e. 100% of the dose makes it into the systemic circulation. For a drug that is administered extravascularly (e.g. orally), the bioavailability will be lower than 100% as there are several possible sites of loss along the way. For example, the oral administration of a drug requires that it be absorbed from the gastrointestinal (GI) tract, from where it must pass through the liver via the portal vein, before entering systemic circulation, Fig. 1.1.6. Degradation of the drug in the gastrointestinal lumen, incomplete release from the dosage form (dissolution), and metabolism of the drug, either in the gut or as it first passes through the liver, are all processes which can contribute to a reduction in the bioavailability. This loss of drug during its first passage through these tissues is known as the first pass effect. Drugs which show extensive first pass effect may require much larger oral than intravenous doses in order to achieve the same therapeutic effect.