Preface

Adverse effects as unwanted outcomes of drug effects occur generally when the upper threshold of therapeutic dosage range is reached. Several events and factors may lower this threshold or bring about the trespassing of the therapeutic level. The relevant events include what happens during the journey of the drug in the body, from its absorption from the site of administration, through its distribution and metabolism, to its elimination from the body. Every chapter in this book discusses and provides illustrations on the theme discussed based on authors' understanding and experience while summarizing existing knowledge. In doing so, each chapter provides a new insight that would benefit a novice as well as a seas‐ oned reader in understanding the mechanisms and risk factors involved in the occurrence of adverse effects of drugs.

Chapter 1 explains the linkages between pharmacokinetic processes and the occurrence of adverse effects. It provides an overview on how through direct actions and interactions drugs produce changes in absorption, metabolism and transformation, distribution in or‐ gans, and elimination from the body. These changes as moderated by individual risk factors such as the genetic makeup, sociodemographic and health status, and lifestyle factors lead to the elicitation of adverse effects observed in clinical practice.

Chapter 2 dwells on the pharmacokinetics of one of the most common beverages world‐ wide, the green tea. This chapter elaborates on how food interactions affect the absorption of catechins and provides some practical illustrations that would help tea drinkers to maximize the benefits of this beverage. It further details how subsequent steps, namely, metabolism, distribution, and elimination, of the catechins take place in the mechanisms underlying these steps.

Chapter 3 illustrates the role of enzymatic transformations that result in the advent of de‐ pressive symptoms in patients suffering from chronic hepatitis C treated with interferon al‐ pha (IFN-α). In this chapter, the findings presented demonstrate how upward changes in concentration in plasma and in other compartments such as in cerebrospinal fluid of trypto‐ phan (TRP)-kynurenine (KYN) and its active metabolites [3-hydroxykynurenine (3-HK), ky‐ nurenic acid (KA), and quinolinic acid (QUIN)] are associated with the severity of depressive symptoms clinically seen as adverse effects of IFN-α. This chapter links up to the first chapter in making an exposé of one of the mechanisms by which pharmacokinetic proc‐ esses lead to the advent of adverse effects.

Chapter 4 shows the major roles of pharmacokinetics in drug development, particularly how pharmacokinetic data are useful in ascertaining the safety profile of drugs under devel‐ opment. It provides technical details of relevant steps and endpoints for each phase of a drug development; in doing so, the chapter demonstrates how pharmacokinetic studies are an important tool used to link exposure to efficacy and safety and how they assist in deter‐ mining the dosages of marketed drugs.

Chapter 5 provides an overview on hepatotoxicity of drugs: how several drugs affect the organ that is responsible for most of the metabolism in the body, the liver. It is noted that metabolism is a key step that achieves two major objectives: firstly, in transforming a nonactive substance or prodrug into active metabolites, it helps in the elicitation of the pharma‐ codynamic action of the drug, and, secondly, in transforming an active drug into inactive hydrosoluble metabolites, it helps in facilitating the elimination of the drug from the body, thereby preventing accumulation that may result in unwanted or adverse effects. This chap‐ ter proposes an approach and a scale that could be used for identifying liver toxicity.

**Chapter 1**

**Provisional chapter**

**Introductory Chapter: Linkages between**

**Introductory Chapter: Linkages between** 

Additional information is available at the end of the chapter

Ntambwe MalanguAdditional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76511

some concluding remarks are presented.

Ntambwe Malangu

**1. Introduction**

**Pharmacokinetics and Adverse Effects of Drugs**

**Pharmacokinetics and Adverse Effects of Drugs**

DOI: 10.5772/intechopen.76511

This chapter aims to elaborate on the linkages between pharmacokinetics and the advent of adverse effects of drugs. It is well known that pharmacokinetics is about the journey of the drug in the body, from its absorption, through its distribution and metabolism, to its elimination from the body. During this journey, after its absorption and distribution, the drug reaches its specific sites where it interacts with its receptors, usually proteins and enzymes, and produces its biological effects; this is known as "pharmacodynamics." The biological effects lead to clinical effects that are observed in patients; this is known as "therapeutics or pharmacotherapeutics." In the following sections, the actions of the body on a drug and the actions of the drug on the body are reviewed in each stage to explain how adverse effects occur. In doing so, the mechanisms and risk factors of adverse effects will be addressed. The next section deals with the absorption, followed by the distribution and excretion of drugs as they relate to the occurrence of adverse effects. A final section will deal with risk factors before

**2. Rates of absorption influence on the occurrence of adverse effects**

For the majority of drugs that are administered by other routes than intravenous injection, they need to overcome several hurdles before they reach the systemic circulation. These include the layers of the outer skin of the body or veins in case of subcutaneous and intramuscular routes or the walls of the digestive system. For drugs administered orally, the active substances must first be released from the dosage from, namely tablets, capsules, and other forms. There will be a reduction of therapeutic effects if there is little absorption, or destruction of the drug by

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Chapter 6 describes the side effects of glucocorticoids; this chapter illustrates how some drugs produce several adverse effects that affect several organs and systems in the body. Glucocorticoids are a classic example of how the usefulness of certain drugs is counterbal‐ anced by high risks associated with their use. The sheer extent of the range of side and ad‐ verse effects from glucocorticoids is a reminder on how narrow the therapeutic window is and why clinicians and patients should be vigilant in monitoring untoward effects of drugs.

Chapter 7 provides an update on the side effects of new antidepressants. Having been hailed as better than the old antidepressants, this review on new antidepressants demon‐ strates how pharmacokinetic parameters played an important role in the discovery of some of these new antidepressants and also how they affect the spread of adverse effects.

As a whole, this book, as a fruit from the collaborative work from several international sci‐ entists, will be a useful resource for researchers, students, and clinicians. Each individual chapter could serve as a prescribed reading for postgraduate students and clinicians special‐ izing in and practicing clinical pharmacology and toxicology, pharmacotherapy and phar‐ macotherapeutics, pharmacovigilance, and toxicovigilance, as well as those involved in clinical research, drug discovery, and development.

It is with a heart full of gratitude that I present to you the team of international scientists who contributed to this volume: Drs. Katherine Dunnington, Natacha Benrimoh, Christine Brandquist, Nadia Cardillo-Marricco, Mike Di Spirito, and Julie Grenier from Celerion, a premier Clinical Research Organization, Nebraska, USA; Dr. Kai On Chu and Prof. Calvin Pang from the Chinese University of Hong Kong; Dr. Yuki Murakami from Doshisha Uni‐ versity, Kyoto, Japan, and Dr. Yukio Imamura from Osaka University Graduate School of Medicine, Japan; Irmak Sayın Alan and Bahadır Alan from the Medical Faculty of Okan Uni‐ versity, Istanbul, Turkey; Alejandra Cano Paniagua and Pedro Amariles from the Research Group on Pharmaceutical Prevention and Promotion, University of Antioquia, Colombia; and Drs. Maria Bogdan, Eliza Gofita, Daniela Cornelia Calina, Adina Turcu-Stiolica, Anca Oana Docea, Tudor Adrian Balseanu, Adrian Camen, Gratiela Eliza Popa, Gabriela Rusu, Ina Cristofor, Liliana Pavel, and Liliana Mititelu-Tartau from the University of Medicine and Pharmacy (Craiova, Galati, and Iasi) in Romania.

Finally, I thank and pass the baton to my three sons, David, Daniel, and Miraciel, whose quality time was diverted to edit this book. Furthermore, I salute and acknowledge the ma‐ jor role played by Marina Dusevic as well as the publishing, production, and editorial teams from IntechOpen®.

> **Professor Ntambwe Malangu** Sefako Makgatho Health Sciences University Pretoria, South Africa

### **Introductory Chapter: Linkages between Pharmacokinetics and Adverse Effects of Drugs Introductory Chapter: Linkages between Pharmacokinetics and Adverse Effects of Drugs**

DOI: 10.5772/intechopen.76511
