One size does not fit all! There is as much genetic variation in the metabolism of drugs, foodstuffs and ingested pollutants as there is in the countenance of humans. Other than identical twins, we each have our facial individual identity and, similarly, each of us metabolizes differently both quantitatively and qualitatively. Our technology has advance to the point that medical science can detect many of the nuances that make us uniquely distinct. This is particularly important so that a physician can prescribe an exact dose of a given drug and particularly when several other medications are given coincidently.
Not only does age, sex, weight, intestinal flora, general health, liver and kidney function alter a patient's response to drugs, but genetic factors must be considered. This information is crucial. Prescription Drug Fatality is the fourth leading cause of death after heart disease, cancer, and stroke. The major determinant involved in the metabolism of drugs, toxins and our hormones is the Cytochrome (CYP) P450 enzymes. The most important of these are CYP2D6, CYP2C9, CYP2C19, NAT2, UGT1A1, DPD, 5HTT, and CYP1A2. The'CYP's is a host of enzymes that use iron to oxidize organic molecules, as part of the body's preparation to dispose of potentially harmful substances by making them more water-soluble. The capital letter indicates the superfamily, and the number before and after, the subfamily.
In humans, CYP3A represents one of the most important subfamilies of the P450 superfamily. The CYP3A subfamily is the most abundantly expressed P450 in human liver, and CYP3A is involved in the biotransformation of approximately 50% of drugs that are metabolized. As a result, drug-drug interactions associated with modulation of CYP3A-mediated metabolism can be of substantial consequence. In the past, it was a trial and error of the dose and the drug we would use. To err could cause not only great harm, but even death of a patient. With this new tool, doctors can take the guess work out of prescribing and do it scientifically.
In addition to our hereditary, the CYPs can be both up-regulated (induced) or down-regulated (inhibited) by other chemicals making it on occasion a complexed proposition for drug deposition. When several competing drugs are use for the same CYP enzyme an Adverse Drug Interaction occurs. At times there are multiple CYPs that work on a drug. For example, adding a hydroxyl group to a medication is the body's strategy to get rid of it and is often followed by joining them to other molecular groups such as glucuronide to increase the solubility even further. Most of the CYP in man is found in the liver, the main organ involved in drug and toxin removal, but a fair amount is also in the small intestine. CYP usually is found in the 'microsomal' part of the cytoplasm (endoplasmic reticulum).
We determine the dose and interaction of not only prescribed drugs, but OTC (over-the-counter) and herbal medicines including those used to treat depression, anxiety, seizures and psychoses; heart disease, cancer, diabetes, and pain. These include medications as Coumadin (warfarin), Prozac, Zoloft, Paxil, Effexor, hydrocodone, Amitriptyline, Claritin, Cyclobenzaprine,, Metoprolol, Tagamet, Tamoxifen, Valium, Carisoprodol, Dilantin, Premarin, and Prevacid (and the over-the-counter drugs, Allegra, and the several NSAIDS).
Almost half of us have genetic variations that affect how we process these drugs. There are four different types of metabolizers, and we all fall into one of these categories for the unpredictable pathways in Cytochrome P450 system. The first type which is the norm, and therefore that person would be an NORMAL Metabolizer and medications prescribed in the usual doses will be handled well by your body. The second type, you would be an INTERMEDIATE metabolizer. This means that you to metabolize the medications more slowly. In this case a lower dosage is needed, and there is a chance of medications building up in your system causing adverse effects. It is especially important to monitor medications if you are in this category. Intermediate metabolizers through the 2C9 pathway, for instance, have an increased risk of bleeding incidences when taking the common blood thinner Coumadin or warfarin. For this reason, screening for CYP2C9 variants may reduce the risk of adverse drug reactions in these patients. The third type is a POOR metabolizer. This type of metabolizer is potentially very dangerous, as there is a great chance for the medication to build up in your system making one very sick, or even death.For example, a poor metabolizer of phenytoin, a common antiepileptic would not be able to process the drug and would actually have toxicity if prescribed this drug. The fourth type of metabolizer is ULTRA EXTENSIVE. In this instance, one would very rapidly excrete the medication. If you were an Ultra Extensive Metabolizer through the 2D6 pathway and one were prescribed a narcotic, there may not be any pain relief because the medication would be metabolized so fast that it would have little or no effect.
PHARMACOGENETIC EFFECT OF CYTOCHROME GENOTYPES
A. PM poor metabolizer, absent or greatly reduced ability to clear or activate drugs.
B. IM intermediate metabolizer. Heterozygotes for normal and reduced activity genes.
C. EM EuMetabolizer or the Normal Metabolizer. The expected result.
D. UM Ultra Metabolizer. Greatly increased activity accelerating clearance or activation.
POPULATION FREQUENCY OF CYTOCHROME P450 (CYP) GENOTYPES
Gene PM IM EM UM
CYP2D6 10% 35% 48% 7%
CYP2C9 2-4% >35% ~60% N/A
CYP2C19 2-20% 24-36% 14-44% 30%
Currently Available Tests:
CYP2D6(cytochrome P450 2D6) acts on one-fourth of all prescription drugs, including the selective serotonin reuptake inhibitors (SSRI), tricylic antidepressants (TCA), betablockers such as Metoprolol and many of the antiarrhythmics. Approximately 10% of the population has a slow acting form of this enzyme and 7% a super-fast acting form. Thirty-five percent are carriers of a non-functional 2D6 allele (half of the gene), especially elevating the risk of ADVERSE DRUG REACTION when these individuals are taking multiple drugs. Drugs that CYP2D6 metabolizes include Prozac, Zoloft, Paxil, Effexor, hydrocodone , amitriptyline, cyclobenzaprine (Flexeril), Coreg, Tagamet, Tamoxifen, and the over-the-counter diphenylhydramine (Benadryl) drugs, Allegra and Claritin. CYP2D6 is responsible for activating the pro-drug codeine into its active form and the drug is therefore inactive in CYP2D6 slow metabolizers.
CYP2C9(cytochrome P450 2C9) is the primary route of metabolism for Coumadin (warfarin). Approximately 10% of the population are carriers of at least one allele for the slow-metabolizing form of CYP2C9 and may be treatable with 50% of the dose at which normal metabolizers are treated. Other drugs metabolized by CYP2C9 include Amaryl, Isoniazid,, Amitriptyline, Dilantin, Hyzaar, THC (tetrahydrocannabinol), NASAIDS, and Viagra.
CYP2C19(cytochrome P450 2C19) is associated with the metabolism of Carisoprodol (Soma), Aprazolam, Dilantin, and Prevacid.
CYP1A2(cytochrome P450 1A2) is associated with the metabolism of Amitriptyline, Resperone, Duloxetine(Cymbalta), Theophylline, Caffeine, Diazepam, Sex Hormones Tamoxifen, and Cyclobenzaprine. Amongst other problems these folks have arrhythmias or get jittery when drinking coffee. Lycopene found in tomatoes reduces the effect of the above drugs and hence need more of a dose.
NAT2(N-acetyltransferase 2) is a secondary drug metabolizing enzyme that acts on Isoniazid, Demnerol, and Azulfidine. The frequency of the NAT2 "slow acetylator" in various worldwide populations ranges from 10% to more than 90%.
DPD (Dihydropyrimidine dehydrogenase) is responsible for the metabolism of Fluorouracil (5-FU), one of the most successful and widely used chemotherapy drugs.
UGT 1A1 (UDP-glucuronosyltransferase) variations can lead to severe even fatal reactions to the first dose of Camptosar (irinotecan).
5HTT (Serotonin Transporter) helps determine whether people are likely to respond to SSRIs, a class of medications that includes Citalopram(Celexa), Fluoxetine(Prosac), Paroxetine(Paxil) and Sertraline
With this tool, no longer is it a trial and error proposition as to what drug and its dose to prescribe, We can now do it scientifically with a much better outcome for the patient. Since our CYP genes do not change, this study is done only once in a lifetime. Although, there are several labratories that do this work. the best and the one that we use is the Seattle based GENELEXR . The test is paid for by most medical insurances and archived on a computer registry to be use with the patient’s permission by their current and future doctor and pharmacist. As a doctor with this science, 21st Century medicine can be practice with a far better outcome than the primitive approach we had taken in the past. Please embrace this technology; it can save your life!