Why Pharmacogenetics Is Important

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Most drugs taken on a daily basis require some enzymatic response for metabolism. Whether making the molecule more water soluble for elimination by the kidneys or changing the molecule in a way to activate it after swallowing — what we call prodrugs — enzymes play a critical role in how one’s body deals with a medication. Add to that the transporters that are necessary to carry the drug to a remote site of action and the receptors that accept the drug, all of which may be genetically defined.

Until very recently, everyone was typically treated as “normal,” that is, as part of that 80% to 90% of the population with whom the drug was tested in clinical trials. However, if you are part of the 10% that might have picked up a bad gene from one of your parents, it could mean a poor response, a disproportionately slower elimination of the drug from your body, or some other unexpected outcome.

For example, the drug codeine is used for pain control. Codeine is a prodrug and it needs an enzyme, CYP2D6, to convert approximately 8% of the dose into morphine. If you have “normal” 2D6 genes from both parents, you should get an appropriate response from the drug. If you got a bad gene from one parent and a good gene from the other, you will have a partial response. Bad genes from both would be no response, but you are still stuck with the side effects. It is also possible to have an exaggerated response to the drug — rapid or ultrarapid metabolism — by converting too much codeine into morphine.

If that’s not complicated enough, Codeine also requires a different enzyme, CYP3A4, to water solubilize the molecule for elimination by the kidneys. Not enough enzyme, and the drug builds up in the system, risking accidental overdose. Too much enzyme, and the drug does not work long enough to be effective. Pharmacogenetic testing takes so much of the trial and error out of prescribing.

When we review a complex medication profile, it’s necessary to not only look at the individual effects of the patient’s genetics on the drugs, but to also account for time where multiple drugs are competing for enzymes in the same pathway. For instance, consider a cardiac patient on both a calcium channel blocker for blood pressure and a statin for cholesterol, a combination we use quite often. Both drugs utilize CYP3A4 for elimination, but if both drugs are taken together, we expect the blood pressure medication will slow the elimination metabolism of the statin to a point where the patient may develop muscle aches and weakness. Unchecked, this may lead into rhabdomyolysis and organ failure. It’s a serious problem with a simple solution: Separate the drugs by a few hours, letting each have its turn at the enzyme. Other cases may not be as easy and may require alternative treatment.

My entire team of board-certified geriatric pharmacists have trained in genomic application as well as enzyme competition and “phenoconversion,” a phenomenon where certain drugs can change the patient’s response to other drugs, making someone with a genetically normal metabolic panel appear “abnormal.” Our science and education department also holds an accredited postgraduate (PGY1) residency program in pharmacogenomics. CT

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