Each week we will aim to bring out a concise email that provides 4-5 key pieces of information addressing a specific issue in clinical therapeutics.
This week: Pharmacogenomics (part 3)
There are many examples of medications where the extent of the pharmacological activity of the drug is profoundly influenced by pharmacogenomic factors that will have impact upon the metabolic activity of CYP enzymes. A drug that is metabolized by a particular CYP enzyme is referred to as a substrate of that enzyme.
- In some cases, the clinical application of and understanding of pharmacogenomics is relatively simple to apply. For example, the anginal drug perhexiline is profoundly dependent upon metabolism through the CYP450 2D6 enzyme – a person who is genetically coded as a slow metaboliser must have a significant dose reduction to prevent life-threatening perhexiline toxicity from occurring.
- In the case of tamoxifen, a drug used for the treatment of breast cancer, metabolism through the CYP2D6 isoenzyme is required to activate the drug. A woman with a slow metaboliser genotype may not respond to tamoxifen treatment, meaning that there are profound implications for the management of breast cancer in that case.
- Another example would be the predisposition of a person to skeletal muscle toxicity such as myopathy, during treatment with statin medications for elevated cholesterol. People with reduced activity of CYP3A4 are at markedly greater risk of these side effects, and a greatly reduced dose of statin medication will be required for these individuals.
- In some cases, genomic variability may influence the expression of a potential drug interaction. For example, when the administration of a drug exerts a moderate inhibitory effect upon the activity of a particular enzyme, this would usually not be significant unless the genomics of that individual mean that they are already prone to reduced expression of the enzyme. This means that pharmacogenomic studies can help to predict the extent to which a drug interaction will manifest in an individual.
Please consider these issues when preparing or interpreting RMMR reports or education sessions. Contributions of content or suggested topics are welcome and should be sent directly to firstname.lastname@example.org.