By DFK | October 29, 2013 at 05:27 PM EDT | 3 comments
After the post on warfarin, I thought now would be a good time to talk about drug-gene interactions. With warfarin as an example, we can talk about a genetic-dynamic interaction and a genetic-kinetic interaction.
The interaction of a drug and a drug target (a target protein) produced by a variant gene (allele), such as a receptor (click here and click on "drug targets" to review the basics of what a receptor is) results in a genetic-dynamic interaction. In this case the "target protein" for warfarin is the enzyme vitamin K epoxide reductase (sub-unit 1); VKORC1. Warfarin inhibits the activation of vitamin K dependent clotting factors by interacting with VKORC1, resulting in decreased clotting. One of the common uses of warfarin is in patients with the irregular heart rhythm, called atrial fibrillation, where the risk clot formation and stroke is increased. Since this is a case of 'what the drug does to the body', i.e., warfarin inhibits clot formation, this is pharmacodynamics. When someone has a genetic variation resulting in decreased formation of VKORC1, such as the *2 variant, and warfarin is used, there is less target enzyme made and it takes less warfarin to inhibit clot formation. The interaction of warfarin with the product of a VARIANT gene is a drug-gene interaction.
The interaction of warfarin and a decreased or loss-of-function form of the (click here and read about drug metabolizing enzymes drug metabolizing enzyme)CYP2C9 produced by a variant gene (e.g. CYP2C9*2, CYP2C9*3), is a drug-gene interaction. Here, since this is the case of 'what the body does to the drug', i.e., CYP2C9 metabolizes warfarin, this is pharmacokinetic interaction.
So a drug has to interact with a product of a variant gene to be considered a drug-gene interaction. If there is a 'normal' gene producing a 'normal' protein drug target, no interaction would be observed.
Here are some gene forms, tell me if a drug interacts with a given gene (you choose), would there be an interaction?
What if a person has one 'normal' gene from one parent and one variant gene from the other parent, would there be a drug-gene interaction? Let us know your thoughts!