Health and DNA: Interpretive Comments

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Interpretive Comments for 2D6, 2C9, and 2C19

The information below can help you understand and apply the results of the DNA Prescription Drug Reaction Test currently offered by Genelex. Our tests spot individual genetic variants in the three most important drug metabolizing enzymes: Cytochrome P-450's CYP2D6, CYP2C9, and 2C19.

More than half of the population has one or more serious defects in the genes coding for these enzymes. Recent research shows that genetic variation in the drug metabolizing system is the singlemost important factor affecting a patient's response to drugs. The information Genelex provides can help you determine the appropriateness and dosage of roughly a third of the most commonly prescribed drugs. To determine if medications are metabolized through these pathways, utilize the following drug list.

Testing places individuals in one of four categories:

· Extensive metabolizers (EM) represent the norm for metabolic capacity. Genotypes consistent with the EM phenotype include two active forms of the gene producing the drug metabolizing enzyme and therefore posses the full complement of drug metabolizing capacity. Generally, extensive metabolizers can be administered drugs which are substrates of the enzyme following standard dosing practices.

· Intermediate metabolizers (IM) may require lower than average drug dosages for optimal therapeutic response. In addition, multiple drug therapy should be monitored closely. Genotypes consistent with the IM phenotype are those with only one active form of the gene producing the drug metabolizing enzyme and therefore have reduced metabolic capacity.

· Poor metabolizers (PM) are at increased risk of drug-induced side effects due to diminished drug elimination or lack of therapeutic effect resulting from failure to generate the active form of the drug. Genotypes consistent with the PM phenotype are those with no active genes producing the drug metabolizing enzyme. These individuals have a deficiency in drug metabolism.

· Ultra-extensive metabolizers (UM) may require an increased dosage due to higher than normal rates of drug metabolism. Simultaneously treating with medication that inhibits metabolization has also proven effective. Genotypes consistent with UM phenotype include three or more active genes producing the drug metabolizing enzyme and therefore have increased metabolic capacity.

Cytochrome P-450 2D6
Phenotype prevalence is 10 % PM, 7% UM, and 35% IM.

Therapy Modification

PM
Avoid medications that are altered to their active form through 2D6, such as opioids. (For instance, 10% of a codeine dose is transformed to morphine through demethylation in the liver.) If you are uncertain, contact the drug manufacturer or look up the pharmacology data.

Reduce dosage 6-10 fold for medications that are administered in their active form and deactivated through 2D6 as are many antidepressants. (Desipramine, for example, is absorbed from the gastrointestinal tract following oral administration and is extensively bound to tissue and plasma proteins in the order of 90-95%. It is inactivated by hydroxylation and by further demethylation in the liver.) If you are uncertain, contact the drug manufacturer or look up the pharmacology data. Therapeutic drug monitoring is recommended for PMs to confirm that steady-state drug concentrations are within the therapeutic target interval.

UM
Increase dosage 2-5 fold depending on the number of duplications noted in the report. Success has also been achieved by concurrently administering another substrate or an inhibitor of CYP2D6.

IM
Start IMs at lowest efficacious dose and avoid multiple drug therapy that inhibits or activates through the same pathway.

Changes in metabolic capacity for an individual does not change the pharmacologic action of the medication. Therefore standard therapeutic drug concentration target intervals can be used to optimize dosage titration. The advantage of knowing the subject's genotype is in predicting the general dosage range for initiation and recognizing changes in time to achieve steady-state for interpretation of blood concentration monitoring.

Therapeutic drug monitoring is recommended in patients with metabolic variations. Keep in mind that subjects with metabolic deficiency will have decreased drug clearance and require additional time to achieve steady-state. In contrast, subjects with increased metabolic activity (UMs) have increased drug clearance and will achieve steady-state sooner that extensive metabolizers.

Cytochrome P-450 2C9 and 2C19
Phenotype prevalence is 3.7% PM, 38% IM for 2C9. Phenotype prevalence is 3% PM (for Asians 15-21%) for 2C19.

Therapy Modification

PM
Reduce dosage 3-5 fold.

IM
Start IM's at lowest efficacious dose, avoid multiple drug therapy that inhibits or activates through the same pathway.

Therapeutic drug monitoring in PM and IM subjects is highly recommended. Again standard measures of efficacy (INR for warfarin or therapeutic target interval for phenytoin, for example) can be applied to ensure optimal therapy.

References

Linder MW, Valdes R Jr. Pharmacogenetics in the practice of laboratory medicine.
Mol Diagn. 1999 Dec;4(4):365-79. Review.
PMID: 10671647 [PubMed - indexed for MEDLINE]

Interpretive Comments for 1A2

The information below can help you understand and apply the results of the DNA Prescription Drug Reaction Test for CYP1A2 currently offered by Genelex.

CYP1A2 Interpretation

Hyperinduction phenotype: 39 - 47% (Japanese, Egyptian, Caucasian)
Drugs metabolized by this enzyme approximately 5-10%
Low affinity/high capacity enzyme

Therapy Modification
Testing places individuals in one of three categories:

Normal Induction represents the norm for induction of metabolic activity in the presence of an inducer. Genotypes consistent with the normal induction phenotype include two CYP1A2 *1A alleles.
Diminished Induction represents a lower than normal level of induction in the presence of an inducer. Genotypes consistent with the diminished induction phenotype are those with either one or two CYP1A2*1C alleles.
Hyperinduction represents a higher than normal level of induction in the presence of an inducer. Induction may be approximately 40% higher in these patients than in those with the normal induction phenotype. Genotypes consistent with the hyperinduction phenotype include one or two CYP1A2*1F alleles. Patients with this phenotype may require an increased dosage of CYP1A2 substrates due to higher than normal rates of drug metabolism in the presence of an inducer.

Doses of CYP1A2 substrates with a narrow therapeutic range should be decreased immediately on cessation of heavy smoking. A stepwise daily dose reduction of approximately 10% until the fourth day after smoking cessation accompanied by therapeutic drug monitoring has been proposed by Faber et al. Clin Pharmacol Ther. 2004 Aug;76(2):178-84.

References:
- Chida M et al., Jpn J Cancer Res 1999; 90:899-902.
- Sachse C et al., Br J Clin Pharmacol 1999; 47(4):445-9.
- Nakajima M et al., J Biochem (Tokyo) 1999; 125(4):803-8.
- Hamdy SI et al., Br J Clin Pharmacol 2003; 55:321-324.
- Eap CB et al., J Clin Psychopharmacol 2004; 24(2):214-219.

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The content of this web site is for public use, free of charge, and for information only. It is not intended to be used in any other way. The authors disclaim any liability, loss, injury, or damage incurred as a consequence, directly or indirectly, of the use and application of any of the content of this web site.

The information presented on this site is intended as general health information and as an educational tool. It is not intended as medical advice. Only a physician, pharmacist, or other healthcare professional should advise a patient on medical issues and should do so using a medical history and other factors identified and documented as part of the health professional/patient relationship.

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Founded in 1987, Genelex Corporation has been accredited by the AABB Parentage Testing Committee in DNA parentage testing since 1992, is Washington State Medical Test Site No. MTS-3919 CLIA No. 50D0980559, and has contributed to the validation of National Institute of Standards and Technology (NIST) Standard Reference Materials.

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