Transcript
0:00Pharmacogenetics
Lesson 4.4 of our metabolism module: genes and metabolism. Metabolism is the chemical change of a drug by enzymes. Elimination is the irreversible loss of the drug from the body, by metabolism or by excretion in urine or bile. For many drugs, metabolism is the main route of elimination, and it usually ends the drug action. A gene, a section of DNA, holds the code for a protein, such as an enzyme. Pharmacogenetics studies how inherited DNA differences change drug response. Each person inherits one version of most genes from each parent, and each version is an allele. The pair of alleles is the genotype. A variant, a difference in the DNA of an allele, can remove, lower, keep or raise the allele function. A duplication places extra gene copies in one allele.
1:10Metabolizer groups
The phenotype is the enzyme activity of a person, and the genotype predicts it. Of the four main groups, a poor metabolizer has little or no activity, and an intermediate metabolizer has decreased activity. A normal metabolizer has normal activity, and an ultrarapid metabolizer has increased activity from extra gene copies or increased-function alleles. When an enzyme inactivates a drug, low activity raises the drug concentration, and when it forms the active compound, low activity lowers the effect. The main example is CYP2D6, one of the cytochrome P450 enzymes, or CYP enzymes. Four parts follow: the activity score, the frequency of each group, the effect of other drugs, and other genes.
2:10The CPIC activity score
The first part is the activity score of the Clinical Pharmacogenetics Implementation Consortium, or CPIC. Each CYP2D6 allele receives an activity value: 0 for no function, 0.25 or 0.5 for decreased function, and 1 for normal function. For an allele with extra gene copies, the value is multiplied by the number of copies. The activity score is the sum of the values of the two alleles. A poor metabolizer has a score of 0, and an intermediate metabolizer has a score of 0.25 to 1. A normal metabolizer has a score of 1.25 to 2.25, and an ultrarapid metabolizer has a score above 2.25.
3:09Frequency of each group
The second part is the frequency of each group. Each allele has a name with a star and a number. In one compilation, the no-function allele CYP2D6 star 4 makes up 18 percent of alleles in Europeans and 0.6 percent in East Asians. The compilation uses an older rule that counts a score above 2 as ultrarapid. From the allele frequencies, it predicts 0.4 to 5.4 percent poor metabolizers and 1 to 21 percent ultrarapid metabolizers across the major population groups. Europeans have the highest frequency of poor metabolizers, and East Asians and Oceanians have the lowest. Oceanians have the highest frequency of ultrarapid metabolizers, at 21.2 percent, and East Asians have the lowest, at 1.4 percent.
4:16Effect of other drugs
The third part is the effect of other drugs. An inhibitor is a drug that lowers the activity of an enzyme. For a patient who takes a strong CYP2D6 inhibitor, the CPIC guideline sets the activity score to 0. For a moderate inhibitor, it multiplies the score by 0.5. The genotype stays the same, and the phenotype changes.
4:45Other genes
The fourth part is other genes. For some heart and brain blood vessel conditions, the CYP2C19 genotype guides the choice between clopidogrel and another antiplatelet drug. The CYP2C9 gene, for an enzyme that metabolizes warfarin, and the VKORC1 gene, for the warfarin target, guide the warfarin dose. The TPMT and NUDT15 genes code for two enzymes that inactivate thiopurine drugs, a group of immunosuppressant and anticancer drugs. These genes guide the initial dose of two thiopurine drugs, azathioprine and mercaptopurine.
5:35Codeine
Codeine shows what the groups mean for a patient. Codeine relieves pain mainly through morphine, which CYP2D6 forms. Plasma is the liquid part of the blood, and serum is plasma without the clotting proteins. Exposure is the AUC, the area under the plasma concentration-time curve. In studies of healthy volunteers, poor metabolizers had a 96 percent lower mean morphine exposure in serum than normal and intermediate metabolizers. A cold pressor test is a pain test with the hand in ice water. In this test, codeine gave poor metabolizers no more pain relief than placebo, a dose with no active drug. In one study, healthy volunteers took a single 30 milligram dose of codeine. The median morphine exposure was 45 percent higher in ultrarapid metabolizers than in normal metabolizers. Sedation, or sleepiness, occurred in 91 percent of ultrarapid metabolizers and in 50 percent of normal metabolizers. One patient developed potentially fatal toxicity after small codeine doses for a cough. He carried three or more functional CYP2D6 gene copies. Other drugs inhibited CYP3A4, which converts part of each codeine dose to norcodeine. This can leave more codeine for CYP2D6 to convert to morphine. His kidney function was also temporarily low, which slowed the excretion of morphine and its products. For normal metabolizers, the CPIC guideline recommends the dose on the product label. For intermediate metabolizers, it recommends the same dose and close checks of pain relief. For poor and ultrarapid metabolizers, it recommends another pain drug.
7:49Summary
In summary, inherited alleles place people in four main groups, and the CYP2D6 activity score assigns the group. The predicted frequency of each group differs between populations. For a patient who takes a strong inhibitor, the guideline sets the score of a poor metabolizer. Other genes guide the choice or dose of clopidogrel, warfarin and the thiopurine drugs. For codeine, poor metabolizers reach a much lower morphine exposure, and ultrarapid metabolizers reach a higher one. The guideline recommends another pain drug for both groups. This concludes lesson 4.4 on genes and metabolism.
Sources
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Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
