Explainers

How Genetics Influences Medicine Metabolism


“We are here to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wondrous map ever produced by humankind.” – President Bill Clinton, July 2000

Objectives

After reading this article, the practising nurse should be able to:

  • Define pharmacogenomics.
  • Define slow, intermediate, extensive and ultra-rapid metabolisers.
  • Elaborate the potential uses of pharmacogenomic testing with respect to drug prescribing and the evaluation of efficacy/toxicity.

Overview

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.

A pharmacogenomic scientist.

The field of pharmacogenomics provides useful clinical information to enhance patient care.

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.

Pharmacogenomics

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.

Molecular structure of cytochrome P450, which belongs to the super-family of proteins containing a heme cofactor.

Molecular structure of cytochrome P450, which belongs to the super-family of proteins containing a heme cofactor.

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:

  • Slow (poor) metabolisers have markedly reduced or no enzyme activity.
  • Intermediate metabolisers have reduced enzyme activity.
  • Extensive metabolisers have normal enzyme activity (the bulk of the population).
  • Ultrarapid metabolisers have high enzyme activity.

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.

Pharmacokinetic Implications

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 and morphine obtained from the poppy plant, Papaver somniferum have been around for millennia.

Codeine and morphine obtained from the poppy plant, Papaver somniferum have been around for millennia.

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.

Test Your Knowledge

Question: Which one of the following statements is not correct?

  • An estimated 20 to 95 per cent of patient variability in response to individual drugs is due to genetics.
  • Pharmacogenetics is the study of the effect of genetic factors on the response of individuals or population subgroups to certain drugs.
  • Pharmacogenomics attempts to 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.
  • A slow metaboliser of a particular prodrug such as codeine will elicit a high therapeutic response.
  • 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.

Scroll down for answer.


Correct Answer

“D” = a slow metaboliser of a drug that needs to be activated will elicit a poor or negligible response.

Show References

Useful References

  • Brunton LL, Chabner MD, Knollmann BC. Goodman & Gilman’s The Pharmacological Basis of Therapeutic 12th edition, New York, 2011.
  • Bryant B, Knights K. Pharmacology for Health Sciences. 4th edition, Mosby, Elsvier, Melbourne, 2015
  • Sheffield LJ, Phillimore HE. Clinical use of pharmacogenomic tests in 2009. Clin Biochem Review 30: 55-65. http://www.genetics.edu.au/Pr[…]cs

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