Pharmacogenetics
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New Web Seminars: Coumadin (warfarin) Genetics and thePrevention of “Oversteer” and Clinical Pharmacogenetics in the Practice of Medicine

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 extensive metabolizer. The norm.
D. UM Ultra Metabolizer. Greatly increased activity accelerating clearance or activation

Population Frequency of Cytochrome p450 (CYP) genotypes

Currently Available Tests

Individualized Patient Reports based on patient drug, herbal and diet regimens

DNA Testing and personalized medicine

ADRs a serious medical problem

The role of genetics in drug metabolism

Ordering Tests

Currently Available Tests
CYP2D6 (cytochrome P450 2D6) is the best studied of the DMEs and acts on one-fourth of all prescription drugs, including the selective serotonin reuptake inhibitors (SSRI), tricylic antidepressants (TCA), betablockers such as Inderal and the Type 1A 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, especially elevating the risk of ADRs when these individuals are taking multiple drugs. Drugs that CYP2D6 metabolizes include Prozac, Zoloft, Paxil, Effexor, hydrocodone , amitriptyline, Claritin, cyclobenzaprine, Haldol, metoprolol, Rythmol, Tagamet, tamoxifen, and the over-the-counter diphenylhydramine drugs, Allegra, Dytuss, and Tusstat. 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) and Dilantin (phenytoin). 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, sulfa, ibuprofen, amitriptyline, Hyzaar, THC (tetrahydrocannabinol), naproxen, and Viagra.

CYP2C19 (cytochrome P450 2C19) is associated with the metabolism of carisoprodol, diazepam, Dilantin, and Prevacid.

CYP1A2 (cytochrome P450 1A2) is associated with the metabolism of amitriptyline, olanzapine, haloperidol, duloxetine, propranolol, theophylline, caffeine, diazepam, chlordiazepoxide, estrogens, tamoxifen, and cyclobenzaprine.

NAT2 (N-acetyltransferase 2) is a second-step DME that acts on isoniazid, procainamide, and Azulfidine. The frequency of the NAT2 "slow acetylator" in various worldwide populations ranges from 10% to more than 90%.

Warfarin (Coumadin)Target Dose Safety Test (2C9 and VKORC1) predicts the maintenance dose of warfarin to within 1.5 mg per day, or less.

Individualized Patient Reports based on patient drug, herbal and diet regimens
DNA test reports can include patient specific information on potential drug-drug interactions (DDIs) mediated by the tested polymorphic drug metabolizing enzymes, taking into account patient dietary, OTC and botanical medicines. Testing patients for drug metabolizing enzyme genotypes can provide physicians with immediate insight into individual differences in their patients' drug processing ability and help them improve the efficacy and safety of the prescribed treatments. This information can be especially valuable when potential drug-drug interactions (DDIs) are a possibility.

DNA Testing and personalized medicine
Genelex's DNA Drug Reaction Tests for the highly polymorphic cytochromes, CYP2D6, CYP2C9, CYP1A2, and CYP2C19. These enzymes process half of the most commonly prescribed drugs, including many with narrow therapeutic indices and frequent participation in drug-drug interactions. (Drug Interaction Principles for Medical Practice, 2nd ed. APPI, 2003) Half of your patients have genetic variations in these genes that lead to altered or absent function resulting in elevated patient susceptibility to adverse drug reactions. Genotyping to avoid ADRs is a dependable tool to improve your practice today and begins your transition to the practice of tomorrow.

ADRs a serious medical problem
In 2000, Genelex began offering physicians an alternative to the "one size fits all" and "trial and error" prescribing of drugs. All too often, a serious adverse drug reaction (ADR) is the result. ADRs are not medical errors, but events that occur in spite of compliance with dosage recommendations. A 1998 meta-analysis of thirty-nine prospective studies in US hospitals estimated that 106,000 Americans die annually from ADRs. (JAMA, 279;1200 1998) Adverse drug events are also common (50 per 1000 person years) among ambulatory patients, particularly the elderly on multiple medications. The 38% of events classified as serious are also the most preventable. (JAMA, 289;1107 2003)

The role of genetics in drug metabolism
It is now clear that virtually every pathway of drug metabolism, transport and action is susceptible to genetic variation. It is estimated that 20 to 95 per cent of individual variability is genetic based. (NEJM 348;529 & 538 2003) Within the top 200 selling prescription drugs, 59% of the 27 most frequently cited in ADR studies are metabolized by at least one enzyme known to have gene variants that code for reduced or non-functional proteins. This compares with 7% of a random selection from the top 200 list. (JAMA, 286,2270 2001) Many other factors such as age, physiological functioning and concomitant disease are known and can be accounted for, leaving the genotype of the patient as a major unknown factor in the prescribing of medicines.

Ordering Tests
Now you can add another dimension to providing safer and more efficacious care to your patients by ordering DNA Drug Reaction Profiles for them. Each pharmacogenetic test is only $250.00, $600 for a standard panel that includes 2D6, 2C9, and 2C19, or $1000 for all five. Five-day stat testing is available for an additional $100. The process couldn't be simpler, we provide you with a cheek swab collection kit and prepaid shipping to return samples to our laboratory. Call 800 523-3080 for more information or to obtain collection kits.