Pharmacogenomics

A Brief Introduction by Yours Truly

You can make a pretty good guess as to the meaning of this page just by looking at its two roots. You surely know what "pharmaco" means by now - having to do with or measuring the action of drugs. And "genomics" sounds like it might be related to genes, or inheritance, or something like that.

"Pharmacogenomics" is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. As usual, Wikipedia's entry is clear and authoritative. The National Library of Medicine features a nice Genetics Home Reference, a portion of which is called "What Is Pharmacogenomics?"

A few other sources of information about pharmacogenomics are a large section in the Human Genome Project site, the University of Utah's Genetic Science Learning Center, and the PHG Foundation's series of interactive tutorials.

It might not seem, at first, that genetic differences in different individuals' subsets of various drug receptors would exert that much of an effect on the manner in which the drug is ultimately used by the body. But it's worth a quick refresher on the factors that govern how well a drug molecule interacts with a receptor. Since drugs do not covalently bind to a receptor (which would result in permanent attachment), their interactions with it must be governed by the same "non-bonded interactions" that you learned about in those wonderful, heady days of first starting to study chemistry - high school or college.

I know these will sound familiar, so I'll just remind you of a few types of weak bonds that molecules can form with each other. The strongest are hydrogen bonds, or "H-bonds"; their average strength is about 1-7 kcal/mol (and that's not much). Less strong than these are attractions between, say, a permanent dipole and an induced dipole, along with many others. The weakest intermolecular forces are called "London Dispersion Forces", also known by many other names, including "van der Waals" forces. A rigorous recall of these different forces and their relative strengths is, fortunately, unnecessary for understanding the topic at hand. If you'd like to review these concepts, assuring that your understanding will be as thorough as possible, please check out ChemTutor - a great site for basic chemistry tutorials.

The most important factor governing how good a "fit" a drug has for a receptor is the drug's 3-D shape. Each receptor has a characteristic shape, and two factors determine how well a drug molecule might fit. First, it must have a complementary shape, so that the drug fits into the receptor a little like a 3D jigsaw puzzle (think of your hand fitting into a perfectly-sized glove). Second, the partial charges in the drug molecule also should line up with the (opposite) charges in the receptor. But fear not; we won't go into it any deeper than that.

The important concept to keep in mind when talking about pharmacogenomics is that the net effect of various receptor types, as well as sub-receptors, is that the speed of the reaction initiated by the receptor can vary dramatically between individuals. This can result in many different outcomes, whose reason is unknown to the patient until s/he or a physician think to get a genetic screening.

An excellent example of this situation, which impacted me personally, is the existence of several different genetic variants of the enzyme responsible for the metabolism of methadone. The largest family of oxidizing enzymes found in the liver are the Cytochrome P450 "superfamily" of enzymes. There are several enzymes that help metabolize methadone, and are classified by a subjective description of the metabolic speed each can cause.

A subset of the P450 enzymes is called CYP2D6, which is primarily responsible for the metabolism of methadone. The normal half-life of methadone is given between 8-15 hrs. - but that's an average. I am in a small minority called the "ultra-fast metabolisers" - I can take 10mg of methadone, and in less than an hour a urinalysis will be clean - no methadone, no metabolites. Ultra-fast metabolisers virtually always have two copies of the enzyme. Other folks can take a small quantity of methadone and still have it show up in a urinalysis days later.

You can probably guess how I learned this about myself. My pain management physician started doing urinalyses for the usual reasons, and we were both amazed when my methadone screen came up empty. Fortunately, I'd been with her for several years already, so she wasn't suspicious of me; she just wanted to solve the problem. It didn't take that much time, actually, to find the likely cause, and a genetic screen confirmed it. Meanwhile, I was seeing how late I could take a 10mg methadone tab and still show up clean.


The methadone example is but one of many, where someone's genetically-determined mixture of metabolizing enzymes can seriously affect their lives.

This is also true for the majority of psychiatric medication, particularly antidepressants. I have a book, published in 2010, called "Psychiatric Pharmacogenomics" (very intense and deep), that illustrates how genetic differences in metabolizing enzymes can affect the efficacy, metabolism, and excretion of many psychiatric drugs. Hopefully, as the science continues to grow and become more commonly discussed, all psychiatrists will become familiar with these important considerations. For instance, it is believed that the variability in people's tendency to become addicted to Valium is genetically-linked. So far, it's more often the patient than the physician who bring up genotyping, but it's become quite inexpensive, so if you think these considerations may apply to you, I encourage everyone to ask their prescribers about genotyping.

This is still a very young science, so progress will probably remain at its current, very rapid pace for several years. What the medicinal chemists are already developing is a future system where all patients would undergo a cheap genetic screening, which would become part of their medical record. Then, if an occasion came to prescribe methadone, the physician could immediately know what kind of metabolizer his patient was, and would also be alerted to other drugs which are metabolized by CYP2D6 and might affect the methadone's metabolic rate.