Cytochrome P450 genetic profiles
From Cafer's Psychopharmacology, available soon from Amazon
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.
Copyright 2020, CaferMed LLC
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.
Here is a cute representation of how a normal individual, i.e., 2D6 extensive metabolizer (EM), processes 2D6 substrates. The air inside the beach ball represents the substrate, which is being expelled from the ball as metabolite at the usual rate. 2D6 substrates will have typical elimination half-lives.
For 2D6 ultrarapid metabolizers (UM), the air (2D6 substrate) flows out of the ball quickly as metabolite. 2D6 substrates could be ineffective for these individuals (with the exception of 2D6 prodrugs, which could be be too strong).
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”.
For 2D6 “POOR ME”tabolizers (PM), air accumulates, resulting in unexpectedly long half-lives for 2D6 substrates. These individuals are more likely to report side effects.
An individual taking a strong 2D6 inHibitor (pump as illustrated on page 15) will metabolize 2D6 substrates as if the individual had a 2D6 PM genotype.
In summary, genetic testing of CYP polymorphisms will interpret the metabolizer profile for a given enzyme as either:
❖ Extensive metabolizer (EM) – normal
❖ Ultrarapid metabolizer (UM) – fast clearance of substrate
❖ 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 about $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, and valproic acid are usually reported the same day.
Copyright 2020, CaferMed LLC
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