Research in the field of molecular biology and clinical medicine has since expanded in studying the variabilities of responses to drugs based on your unique gene sequences. This is referred to pharmacogenetics or in a broader context, pharmacogenomics.
Recent findings have discovered that up to 95% of variability in treatment is due to genetic factors and although being insignificant, other accounts such as cultural, behavioral, and environmental also have an impact on drug metabolism and our body responses. After comprehensive research and the widening of pharmacogenetic studies, we now know that genetic variability has relevance for therapeutic sensitivity, dosing, hypersensitivity to medications and other side effects. Since 1930, this topic of interest on pharmacogenetics or pharmacogenomics has opened a future to novel clinical therapeutic deliveries and is now a big part of precision medicine.
A real-life case of how genes change the response to medication
Differences in drug metabolism between individuals is one of the greatest areas studied in pharmacogenetics. To put this science in context, let’s look at a real-life case on how variability in genetics can affect responses to drugs.
In April 2005, a new mother had given birth to a healthy male infant. To ease some of her post labor episiotomy pain, her doctor prescribed a combination of codeine and paracetamol for 2 weeks. On day 12 post birth, her child turned grey and was pronounced dead by day 13 with high levels of morphine found in his serum sample. After an analysis with a morphine assay, the mother’s breast milk was surprisingly highly concentrated with morphine which led to the death of her baby.
How was this possible?
Before the answer to this unfortunate phenomenon, we must first understand that, following consumption, most drugs are metabolized and structurally modified by enzymes in the body to reach its active or inactive form. There are several players important for this metabolizing process and these players are collectively referred to as the cytochromes P450 enzymes. These cytochromes are in charge of drug oxidative metabolism or commonly known as Phase 1 metabolism in a range of drugs. Seven of these cytochromes P450 are responsible in metabolizing 80% of the medications.
Let’s focus on one of the seven cytochrome: CYP2D6.
The CYP2D6 consists of many genetic variants or “alleles” and each allele codes for an enzyme with slightly different structure and function. Every individual will acquire a combination of 2 CYP2D6 alleles from both parents which determines their ability to metabolize certain drugs. Some people actually have a combination of 2 non-functional alleles due to the presence of variant alleles that codes for its inactive form. This classifies them as “poor metabolizers”, meaning they will most likely have a harder time to activate the drug and hence, do not respond efficiently to the medication. In most cases however, people have a decent amount CYP2D6 activity and are termed “normal” (1-2 normal functional alleles) or slightly decreased which referred to as “intermediate metabolizers” (2 or more decreased functional alleles or 1 functional allele and 1 un functional allele).
Interestingly, rare individuals will have three functional alleles, hence above normal metabolism rate, which will classify them as “ultra-rapid metabolizers”. This is in fact the cause for the morphine poisoning report mentioned earlier.
After a genotype analysis, the mother was found to be heterozygous for CYP2D6*2A allele and CYP2D6*2X2 gene duplication. This classifies her as an “ultra-rapid metabolizer” where the codeine was transformed to morphine at a more rapid rate than “normal metabolizers”. Excess morphine that was metabolized in her body was subsequently transferred into her breast milk and caused opioid intoxication, resulting in the death of her son through indirect overdose.
Future of medication through Pharmacogenetics
Codeine is by no means a harmful drug. It is an effective pain killer when being prescribed to the right person at the right time. After this incidence, codeine has been confirmed unsafe by the Food and Drug Administration (FDA) for infants during breastfeeding. Further, the FDA has now included pharmacogenetic information and drug-gene association in over 200 medications. This light in pharmacogenetic relevancy has offered guidelines for practitioners to tailor suitable medication with correct dosing and information for their effectiveness based on your gene variation. More pharma companies are also using pharmacogenetic insight to develop and market drugs for specific genetic profiles to maximize drug benefit and speed up recovery processes.
Expanding the pharmacogenetic research has revolutionized therapeutic deliveries by personalizing medicine according to your gene profile. This unconventional approach promises to avoid adverse reactions similar to the case report discussed above. For example, there are now guidelines with dosing criteria for codeine prescription in context of CYP2D6 genotypes and also pain killers alternative to opioids for those classified as ultra-rapid metabolizers.
This study is important not only to optimize drug therapy but also precision methods to maximize health benefits according to gene variants.
Although pharmacogenetic research is still quite new and presently available for specific drugs, it has highlighted the importance on investigating the dynamics between drug and individual genetic variants. We can now learn whether drugs we are currently taking or about to take are suitable for us ahead of time to optimize therapeutic outcomes or prevent adverse events. Here at Nalagenetics, we offer NalaXReadyTM and NalaRisk PredictionTM, a genetic test to help assess the right drug for you and analyze your susceptibility to inheritable diseases, respectively. We are capable of classifying whether you, like the mother in the case report, are ultra-rapid metabolizers of codeine. This will help you and your physicians determine alternatives to painkillers and better options to manage your overall health. Contact us at 08119941440. for more information. We will be happy to assist.
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