Polymorphisms, continued

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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.”
A polymorphism with potentially disastrous consequences produces deficient activity of CYP2C9. Patients with this enzyme variant are ineffective at metabolizing phenytoin and tolbutamide, both potentially very toxic drugs in excess. The parent drug will remain in the 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.