CYP GENETIC PROFILES
Genetic polymorphisms can influence an individual’s medication kinetics, which is most relevant for 2D6 and 2C19. Let’s talk about 2D6, arguably the most consequential example.
Most individuals are genetically equipped with 2D6 genes that produce normal 2D6 enzymes that metabolize 2D6 substrates at the usual rate. These normal individuals are said to have a 2D6 extensive metabolizer (EM) genotype, resulting in a 2D6 EM phenotype.
About 5% of the population have extra copies of 2D6 genes, resulting in an ultrarapid metabolizer (UM) phenotype. These individuals clear 2D6 substrates quickly.
About 10% of individuals have defective 2D6 enzymes resulting in a 2D6 poor metabolizer (PM) phenotype. This condition may be found on a diagnosis list as “Cytochrome P450 2D6 enzyme deficiency”.
In summary, genetic testing of CYP polymorphisms will interpret the individual’s metabolizer profile for a given enzyme as either:
Extensive metabolizer (EM) - normal
Ultrarapid metabolizer (UM) - fast clearance of substrates
Poor metabolizer (PM) - slow clearance of substrates
A genetic test result of intermediate metabolizer (IM) means that enzyme activity is likely to be a bit lower than that of an EM, i.e., an intermediate between EM and PM. Generally, IM individuals can be clinically managed normally, like an EM individual.
Standalone 2D6 genotyping costs at least $200. GeneSight or Genecept panels cost about $4,000 and report the six relevant CYPs and two UGT enzymes (UGT1A4 and UGT2B15). 23andMe ($199) reports 1A2, 2C9, and 2C19, among 100s of other genes. 23andMe does not report the most relevant CYP genotype, 2D6, because the genetics of 2D6 metabolism is more complicated.
Genotyping may be useful when choosing which medication to prescribe an individual patient. With GeneSight, about 1 in 5 patients have a genetic variation relevant to their treatment. For an individual already established on a medication, serum drug levels may be more useful than genotyping. There are situations when knowing the actual blood levels of clozapine, risperidone, olanzapine, aripiprazole, haloperidol, lamotrigine, etc. are clinically relevant. Unfortunately, these tests usually must be sent to an outside lab, and it may take a week to see the results. Levels of lithium, carbamazepine, phenytoin, and valproic acid are usually reported the same day.