Pharmacogenomics: Why Drugs Don't Work as Well as We'd Like

We live in a world of massive scientific breakthroughs. In such an age of discovery and innovation, it is frustrating to learn that things never work as well as they theoretically should - as it turns out, the world doesn't exist in a vacuum. Pharmaceuticals are no different. According to the Journal of the American Medical Association, there are over 100 000 deaths a year in the U.S. attributable to adverse drug reactions. Is there some way we could predict (and eventually prevent) ADRs? Well, yes.

Are the medications you're taking harming you
because of your genetic make-up?

That's where the study of pharmacogenomics comes in: by studying the common polymorphisms (genetic variants) related to the particular metabolic effects of drugs, we can alter individual pharmacotherapy approaches to better suit each patient. How is it that genetic variation can lead to different drug effects? There are two frameworks for understanding how genotype and phenotype interact: pharmacokinetics and pharmacodynamics. Pharmacokinetics refers to how the body absorbs, metabolizes, distributes, and excretes drug products. For example, variation in the gene that codes for an enzyme that actives a drug could cause the enzyme to more or less likely to bind to the drug target. This could change the rate at which the drug becomes therapeutic. The second framework, pharmacodynamics, refers to the drug targets themselves - ion channels, receptors, enzymes, and the immune system. For example, variability in an ion pump that expels toxic drug by-products from the cell can alter the rate at which an individual experiences damaging side-effects. 

For a real example, take the opiate analgesic (painkiller) codeine. Codeine is a pro-drug, meaning it must be activated by enzymes in the body before it takes effect. The conversion of codeine from its inactive form to its active form (morphine) is accomplished by the activity of the enzyme CYP2D6, a member of the cytochrome P450 superfamily responsible for drug metabolism and bio-activation. Genetic variation in the region of the genome encoding the CYP2D6 enzyme can greatly alter codeine's efficacy. An allele that causes decreased affinity of the enzyme for its drug target would prevent the drug from reaching its full analgesic effects. Conversely, if the enzyme was super-active and metabolized the drug too quickly, there may be no analgesic effect at all. If we were able to genotype each individual for polymorphisms in the CYP family of enzymes, we could predict which drugs would be most effective, and at which dosages. 

Enter the evolving world of personalized medicine. With human genomics rapidly advancing, some day it may be quite possible to get a personalized profile of which drugs at which dosages you respond best to. It sounds a bit like science fiction, but really, we're not that far off.