Knowledge of the genetic basis of individual drug response is of major clinical importance. Cytochrome P450 (CYP P450) enzymes are essential for the metabolism of many medications. CYP2D6 is involved in the breakdown of almost 25% of commonly prescribed drugs, including Tamoxifen and antidepressants.

Knowing in advance how the patient’s body is likely to metabolize certain medications could significantly improve the chance of prescribing the right medication at the right dosage. CYP2D6 genotyping is most useful for excluding the use of medications that will not be effective or may cause side effects. The test only assesses some of the genetic variations involved in metabolizing drugs. Between 7-10% of women with breast cancer do not receive the full benefit of tamoxifen treatment due to less functional forms of the CYP2D6 gene, which may prevent the conversion of tamoxifen to its active metabolites. Such reduced effectiveness of tamoxifen due to genetic variation increases the chance of breast cancer recurrence.

Several research studies have confirmed worse clinical outcome in patients with decreased CYP2D6 metabolism. In a 6-year follow-up study it was shown that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of non-functional or reduced-function alleles with worse clinical outcomes. CYP2D6 allele 4 is also associated with statin-induced side effects in patients with high cholesterol levels. These include muscle pain, myalgia, creatinine kinase elevations without pain with myolysis and myositis (rhapdomyolysis), a potentially fatal side effect. Adverse drug response has an impact on patient compliance and consequently health outcomes; therefore the assessment of risk on an individual level could enhance therapeutic benefit.

Antidepressants cause severe reactions in about 8% of users, and moderately severe reactions in approximately 30% of people who take them, partly due to mutations in genes encoding CYP2D6. CYP2D6 genotyping divides people into four main groups due to the combined effect of gene-drug interaction: 1) Normal metabolizers process certain medications normally and are therefore more likely to benefit from treatment without any serious side effects; 2) Intermediate metabolizers have at least one gene involved in drug metabolism that does not function normally; this may lead to less effective processing of certain medications compared with normal metabolizers; 3) Slow metabolizers process certain drugs more slowly than normal, leading to build up of certain medications with the potential for serious drug side effects; 4) Ultrarapid metabolizers process certain medications so fast that they leave the body before having a chance to work properly. Women with non-functional CYP2D6 alleles taking Tamoxifen for the treatment or prevention of recurrence of breast cancer, who also use antidepressants such as paroxetine and fluoxetine for depression or hot flashes, may not derive the full benefit of anti-cancer treatment due to drug-drug interaction. It has been estimated that 20-30% of patients taking Tamoxifen are using antidepressants.

Pharmacogenetics based drug selection and dose adjustments are an important tool that can be used to individualise drug treatment according to genetic factors. CYP2D6 genotyping provides a way to assess such gene-drug interaction. 1) With introduction of the CYP2D6 genotyping doctors can more accurately predict which medications would be of no benefit to a patient due to impaired metabolic activity. 2) CYP2D6 genotyping provides an indication of which drugs are more likely to be effective based on the patient’s metabolism, but cannot predict how effective a particular drug will be. 3) Poor or slow metabolizers usually require lower doses to achieve the desired effects and to prevent the occurrence of adverse drug reactions at normal dosages. 4) CYP2D6 genotyping may be of value in selecting adjuvant hormonal therapy. In women treated with tamoxifen to reduce the risk of breast cancer development or recurrence, use of aromatase inhibitors is a reasonable alternative in poor drug metabolizers. Raloxifene is metabolized by glucuronide conjugation. 5) CYP inhibitors which include several antidepressants should be avoided in tamoxifen treated women due to drug-drug interaction which may reduce the effectiveness of anti-cancer treatment. 6) It is important to keep in mind that many factors besides the genetic make-up plays a role to determine drug response.

Combining service with research:

This genetic testing service is combined with research to enable us to monitor the success of a wellness initiative in collaboration with the referring physician. Patients will be assisted to sign the research informed consent form that will be provided together with a saliva sample collection kit. EDTA blood (purple top tube) can also be provided for the genetic test. Patients are encouraged to contact Professor Maritha Kotze (maritha@sun.ac.za / info@gknowmix.com;  tel. 27 21 9389324 / 0828799108) with any questions they may have about the research or the genetic test payment.

A quote for the amount due will be emailed to you once the service request has been entered into the Gknowmix service delivery system and a notification sent to your doctor by email. Please provide the contact details of the referring clinician for participation.