Discussion
Enzymes within the CYP family are important for the metabolism of many drugs. These enzymes show large individual differences in phenotype. This may be related to genetic conditions, diseases and intake of enzyme inhibitors or inducers. Genetic differences are typical for CYP2C9 and CYP2D6, where inherited mutations usually lead to a reduced or defect metabolism (6) .
The patient turned out to be a homozygous carrier of mutations that code for slow metabolism via CYP2C9 and CYP2D6. Four of the prescribed drugs are metabolised extensively by CYP2C9 (warfarin, losartan and glimepiride) or CYP2D6 (metoprolol) (4) . Losartan is a prodrug and is activated by the enzyme in question, while the three others are administered in a pharmacologically active form and become inactivated (fig 2). Clinically this means that the patient had a reduced formation of active losartan metabolite (probably less than 10 of the normal) and thereby insufficient angiotensin II blockade (5) . For warfarin, glimepiride and metoprolol a slow metabolism means a high concentration in relation to the administered dose (about five to ten times higher than normal) and thereby an increased risk of adverse events (4) . Warfarin is a drug with a narrow therapeutic window and increased bleeding risk with elevated INR values, but no sign of bleeding was observed in the patient.
Figure 2 Schematic presentation of the CYP metabolism that was strongly reduced in our patient
Insufficient angiotensin II blockade of losartan because of slow metabolism coincided with a deterioration of the heart failure that was observed at control five weeks after changing from the ACE inhibitor ramipril. At the same control a thrombus was observed in the left ventricle. It cannot be excluded that worsening of the heart failure was a result of the thrombus, but we consider lack of angiotensin II inhibition after the switch to losartan to be a more probable cause. In that case one may speculate whether the lack of an effect from losartan also caused the thrombus and the need for treatment with warfarin.
The reason for requesting the pharmacogenetic CYP analysis was the persistently high INR value after the starting doses of warfarin. The test result confirmed that a high INR value was caused by a genetic slow metabolism of warfarin and not by other factors such as lack of compliance or interaction with other drugs, foods or herbal medicines. The clarification probably contributed to alleviating a stressful situation, not least for the patient. It also gave further grounds for treatment with warfarin requiring that special precaution is taken with dose changes, other treatment and food. In addition, the test answer increased our understanding of the other drugs that the patients were treated with. Losartan was replaced by another angiotensin II receptor antagonist, while a metoprolol dose low enough to be tolerated seemed like a rational choice.
CYP mutations are stable throughout life. Information from pharmacogenetic analyses therefore has a prospective value for choice of possible drug treatment. Comorbidity with heart failure is common and it is reasonable to assume that the information may become useful for our patient later. However, there are challenges associated with the flow of information and knowledge about clinical use of results from pharmacogenetic analyses in the health services. Out-patient follow-up may contribute to solving these challenges through continuous assessments of health status and drug use.
The Journal of the Norwegian Medical Association No. 18/2006 had pharmacogenetics as a theme and focused on individual adaptation of treatment as a vision for the future. CYP genotyping is currently a routine analysis in several Norwegian laboratories and a tool for rationalizing choice of drug and dose to each patient. However, the cost-benefit of CYP genotyping is debated and a core question is to what extent the tests should be used. Questions that concern health priorities are complicated and difficult, but it is interesting that some hospitals in Denmark have established routine CYP genotyping of all admitted patients (7, 8) . This is done from the perspective that investment in this one-time test will be cost-effective in the long run in the form of fewer adverse events, less need for follow-up, better treatment effect and fewer admissions. A prerequisite for such analysis to be useful is the existence of concrete recommendations on choice of drug and start dose for patients with different CYP genotypes (9) .
CYP genotyping consists of about ten separate mutation analyses with a total cost that corresponds to that for three months use of losartan (based on today’s costs). In our case, the treatment with losartan was probably ineffective and may have caused extra admissions and treatment needs. This illustrates that a one-time investment in CYP genotyping may be economical and health- promoting in some patients, but that there is still a need for research to evaluate the usefulness in a larger scale (10) .