Polymorphisms, continued

This version of the course is no longer available.
Need multiple seats for your university or lab? Get a quote
The page below is a sample from the LabCE course . Access the complete course and earn ASCLS P.A.C.E.-approved continuing education credits by subscribing online.

Learn more about (online CE course)
Polymorphisms, continued

Many drugs are metabolized by CYP2D6, whereas much fewer are metabolized by CYP2C19. 5-10% of the Caucasian population are CYP2D6 "poor metabolizers," while approximately 20% of the Asian population are CYP2C19 “poor metabolizers.”
Let's briefly discuss the example of CYP2C9. Normal enzyme function for CYP2C9 (aka wild-type) is given the name CYP2C9*1. The two most common variants; CYP2C9*2 (p.R144C) and CYP2C9*3 (p.I359L) cause significant reductions in enzyme activity of 30% and 80%, respectively. Approximately 1% of Caucasians are homozygous for the *2 variant; 0.4% are homozygous for *3. Heterozygous carriers for CYP2C9*2, CYP2C9*3, and CYP2C9*2/*3 represent 22%, 15%, and 1.4% of the population, respectively. So it's clear that these polymorphisms are common enough to warrant attention. Patients with enzyme variants that are ineffective can have adverse drug reactions with phenytoin and tolbutamide, both potentially very toxic drugs in excess. In such cases, parent drug will remain in circulation for a longer period of time, resulting in toxicity.
CYP2C9 also catalyzes the metabolism of warfarin. In a patient with a CYP2C9 polymorphism, a normal dose of the drug could result in the patient being anticoagulated to the extent of possible hemorrhage. Therefore, patients with a CYP2C9 polymorphism will be prescribed a lower dose of warfarin to achieve optimal anticoagulation. Warfarin is unique in that its metabolism can be impeded by not only a CYP2C9 polymorphism but also by a second genetic variant involving the enzyme VKORC1. VKORC1 is responsible for the conversion of vitamin K epoxide to vitamin K. Vitamin K is a required co-factor for a number of clotting proteins. Warfarin acts as an inhibitor of VKORC1, which leads to a reduced amount of vitamin K available to serve as a cofactor for these clotting proteins.