How Genetics Influences Medicine Metabolism
Published: 10 December 2015
Published: 10 December 2015
After reading this article, the practising nurse should be able to:
Patient response to drugs varies widely and the reasons for this are diverse and complex. It is estimated that genetic factors account for 20 to 95 per cent of patient variability in response to individual drugs.
Genetic influences on drug metabolism interact with other factors, such as: age, gender, race/ethnicity, disease states, concomitant medicines and social factors, determining the outcome from treatment with any pharmacological agent. There is some confusion as to which term to use – pharmacogenetics or pharmacogenomics?
Pharmacogenetics is the study of the effect of single-gene genetic factors on the response of individuals or population subgroups to certain drugs.
Pharmacogenomics evaluates genetic differences within a population that explain certain observed responses to a drug or susceptibility to a health problem, and involves a larger genome approach that considers not only single-gene effects but also multi-gene interactions and pathways.
The aim of pharmacogenomics is to enable the prescribing of drug therapy to be genetically guided, thereby optimising its effectiveness and reducing adverse side effects.
The recognition that most human drug responses are multifactorial has led to the realisation that personalised or individualised medicine implies a broad consideration of factors and thus has resulted in the frequent use of the broader term pharmacogenomics. However, for all intents and purposes, the terms are more or less synonymous and tend to be used interchangeably.
The field of pharmacogenomics provides useful clinical information to enhance patient care and offers a growing potential to individualise drug therapy and improve clinical outcomes.
Many medicines are metabolised by the cytochrome P450 super-family of enzymes. The term ‘cytochrome P450’ is a generic term for the entire family of enzymes. Under this system, the P450 enzymes are divided into families and subfamilies. The activity of metabolising enzymes such as the cytochrome P450 is influenced by a variety of factors, including genetic differences between people, enzyme inhibition and induction, diet, health status, gender and age.
The effect of genetic polymorphisms (differences) on catalytic activity is most prominent for three isoforms: CYP2C9, CYP2C19, and CYP2D6, which collectively account for about 40 per cent of drug metabolism mediated by cytochrome P450.
Patients who have some enzyme activity are classified into four subgroups:
The distribution of CYP2D6 phenotypes varies with race. For example, the frequency of the phenotype associated with poor metabolism is 5 to 10 per cent in white populations but only about 1 per cent in Chinese and Japanese populations. There are also further differences between other racial groups. Similarly, there are variations in activities of CYP2C9 and CYP2C19 enzymes.
Pharmacokinetics is the study of the rate and extent of drug absorption, distribution, metabolism, and excretion (ADME). A combination of metabolism and excretion constitutes the process of drug elimination from the body.
The main routes of drug elimination are metabolism (often in the liver) and renal excretion. Genetic polymorphisms have been identified for many drug-metabolising enzymes, including the cytochrome P450 (CYP450) enzymes. This gives rise to distinct population phenotypes of persons who have metabolism capabilities ranging from extremely poor to extremely fast. Some potential clinical consequences of these polymorphisms are exemplified below.
Codeine is a prodrug (it must be activated by the CYP2D6 enzyme to form morphine (~about 10 per cent of the codeine dose is converted to morphine). Poor to intermediate metabolisers will only convert small amounts of the codeine, hence leading to poor drug efficacy (pain relief), whilst ultra-rapid metabolisers may convert larger amounts of codeine to morphine, leading to morphine toxicity.
Other examples of prodrugs (inactive) that need to be converted to active metabolites include venlafaxine (CYP2D6), clopidogrel (CYP2C19), tamoxifen (CYP2D6), oxycodone (CYP2D6), aripiprazole (CYP2D6) and amitriptyline (CYP2D6).
Where a drug is in the active form, it must be metabolised to form inactive metabolites so that they can be eliminated by the kidneys. Poor metabolisers will only convert small amounts of the parent compound to inactive metabolites, hence leading to possible drug toxicity, whilst ultrarapid metabolisers may convert larger amounts of the parent compound leading to poor efficacy. Examples include: omeprazole (CYP2C19), sertraline (CYP2C19), diazepam (CYP2C19).
Pharmacogenomic tests are now available in Australia, accessible via the usual pathology laboratories, that determine an individual’s fast, moderate or slow metabolism status of the above (as well as others) P450 enzymes. This then enables the prescriber to choose the right drug to maximise efficacy and minimise adverse effects.
Hence, if you notice patients showing a poor or exaggerated response to a medicine, consider discussing with the prescriber about the possibility of having a pharmacogenomic test done.
Question: Which one of the following statements is not correct?
Scroll down for answer.
“D” = a slow metaboliser of a drug that needs to be activated will elicit a poor or negligible response.
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Louis Roller has been an academic at the Faculty of Pharmacy and Pharmaceutical Sciences Monash University for 56 years. He was on the Pharmacy Board of Victoria for 22 years and has significantly contributed to many editions of various pharmaceutical compendia, including the Therapeutic Guidelines. He has been and is on the editorial board of the Australian Pharmaceutical Formulary and Handbook and has contributed significantly to all three editions of Mosby’s Dictionary Medicine, Nursing and Allied Health Sciences. He is the author of hundreds of scientific and professional articles and has a passion for evidence-based knowledge and writes articles on disease state management. He lectures to pharmacists, medical practitioners, nurses, podiatrists and optometrists on a variety of therapeutic topics, as well the University of the Third Age on various medication-related issues. He still lectures to pharmacy undergraduates on a number of topics. He has particular interests in drug interactions and pharmacogenomics and William Shakespeare. He has served as a committee member of the Pharmaceutical Society of Australia, Victorian Branch since 2008. In 2012, he was made a life member of the Australasian Pharmaceutical Sciences Association and, in 2014, he was awarded the life-long achievement award of the Pharmaceutical Society of Australia. His current activities include singing in a choir, visiting schools about bullying (Courage to Care), and giving talks to U3A groups and appropriate accommodation groups. He is a proud member of the Australian Skeptics. See Educator Profile