Pharmacogenetics
Scientific background
Introduction
2.1 This chapter explains how genetic variation can affect response to medicines, and uses case
studies to illustrate how information about such genetic variation can be applied to improving the safety and efficacy of medicines. We first describe the context for the modern development of pharmacogenetics.
2.2 Variation between individuals in their response to medicines has long been evident, and has
posed significant challenges to scientific approaches in pharmacology. Sir William Osler observed in 1892 that ‘if it were not for the great variability among individuals, medicine might as well be a science and not an art.’1
In the 1950s, it was shown that some adverse
reactions to certain medicines were caused by genetic variations that affected the metabolism of the medicine in the body.(2) In 1959, the term ‘pharmacogenetics’ was introduced to describe this phenomenon (see Boxes 1.1 and 2.1 for further definitions of the terms used in the Report).3
2.3 The Human Genome Project was established in 1990 to coordinate research that had been under way for some years to identify all the genes in human DNA. The map of the human genome, which identified the majority of the estimated 30,000-40,000 human genes, was completed in 2003. Scientists have made considerable advances in understanding how DNA functions, and how differences in DNA may lead to differences between people. These differences concern normal variation such as eye colour, or variation that causes diseases, such as cystic fibrosis or Huntington’s disease. Researchers who have begun to examine the genome in more detail are now gaining a deeper understanding of how some variation between individuals in their responses to medicines can be explained in genetic terms.
2.4 This is a challenging enterprise, since the way in which medicines work in the body is complex (see Box 2.1). A number of different genes may be involved in the metabolism and processing of a particular medicine, and may affect different components of these processes. Environmental factors such as exposure to other medicines or chemicals can also influence the effectiveness of medicines, as can the health of the individual. For example, people with poor liver or kidney function are likely to differ from healthy people in how their body responds to a medicine. The compliance of patients with dosage schedules is also important; many failures or unexpected responses to medicines result from patients not taking the right amount of the medicine at the right time under the prescribed conditions. Medicines can even interact with common foods, for example, the consumption of grapefruit juice has been shown to influence the efficacy of some medicines.(4) All of these factors need to be taken into consideration if patients are to benefit fully from the medicines they are prescribed.
2.5 It is unrealistic to expect that by understanding the effects of genetic variation alone it will be possible to eliminate adverse reactions to medicines, or to ensure that we can all be treated more effectively. Research in pharmacogenetics is often welcomed as a step towards ‘personalised’ medicine. While this may be true in the sense that patients may be prescribed one medicine rather than another, or have the dosage of their medicine decided on the basis of information about their genetic make-up, it should not be taken to mean that individual patients will have medicines tailor-made for them. Moreover, one implication of developments in pharmacogenetics may be that some patients learn that it is very unlikely that the medicines available to treat their condition will be effective for them. In talking of personalised, targeted or tailor-made medicine, it is important not to mislead or to overestimate the possible benefits of pharmacogenetics.
| Pharmacology is the study of how a medicine acts in the body. It involves the consideration of both pharmacokinetics and pharmacodynamics. |
| Pharmacokinetics is the study of the processes and rate at which a medicine passes through the body: |
| Absorption is the process by which a medicine enters the blood stream. |
| Distribution refers to the transportation of a medicine to the site of action. |
| Metabolism is the process whereby a medicine’s structure and properties are altered, generally inactivating it and enabling it to be excreted by the body. |
| Excretion is the removal of the medicine from the body through the kidneys and liver. |
| Genetic variation may influence all of these processes, since they involve numerous different molecules produced by genes, such as transport proteins and pumps, carriers and enzymes. Research in pharmacogenetics has traditionally focused on individual variation in the metabolism of medicines. The process of metabolism generally takes place in the liver where medicines are acted upon by enzymes. Variation in the rate of metabolism of a medicine by an enzyme can substantially alter how a person responds to that medicine. For example, rapid metabolism of a medicine can cause it to be ineffective, and slow or non-metabolism can lead to the accumulation of toxic amounts of the medicine in the body (See Box 2.2: Case study 1). Variation in proteins that metabolise medicines often affects response to more than one medicine. |
| Pharmacodynamics is the study of how a medicine works in the body. Most medicines work by interacting with the control systems of the body such as receptors, carrier molecules or enzymes. An individual’s reaction to a particular medicine is therefore affected by genetic variation in these molecules. Historically, the development of medicines has proceeded on the presumption that these molecules are genetically homogeneous in the patient population. However, many studies in recent years have shown that this is not necessarily the case. |
1 Quoted in Roses AD (2000) Pharmacogenetics and the practice of medicine, Nature 405: 857-65.
2 This phenomenon was described in Motulsky A (1957) Drug reactions, enzymes and biochemical genetics, JAMA 165: 835-7.
3 Vogel F (1959) Moderne probleme der Humangenetik, Ergeb Inn Med Kinderheilkd 12: 52-125.
4 Ameer B and Weintraub RA (1997) Drug interactions with grapefruit juice, Clin Pharmacokinet 33: 103-21; Bailey DG et al.
(1998) Grapefruit juice–drug interactions, Br J Clin Pharmacol 46: 101-10. For a summary see UIC College-of-Pharmacy Drug
Information Center Grapefruit Juice Interactions. Available: http://www.uic.edu/pharmacy/services/di/grapefru.htm. Accessed
on: 14 Nov 2002.