Pharmacogenetics

Pharmacogenetics deals with the influence of genetic variation on the effects of medicines. Therapeutic effects as well as side effects of a drug can vary due to the genetic make-up of the recipients. Genetic variation in non-human organisms is not considered in this report.

Genetic differences can result in considerable variation in the rate at which a given medicine is broken down within a patient’s body. The metabolism may take longer than anticipated, thereby increasing the risk of side effects. In case of high metabolic rates the therapeutic effect may be diminished or absent. Metabolic rates depend mainly on cytochrome P-450 and N-acetyltransferase enzymes. Patients may be classified as fast or slow metabolizers, depending on the activity levels of these enzymes. The best known of the cytochrome P-450 enzymes is CYP2D6, which plays a part in the metabolism of beta-blockers, antidepressants and other drugs. About 8 per cent of the Dutch population have a low CYP2D6 activity. Other cytochrome P-450 subtypes also result in delayed metabolism of certain medicines. Slow N-acetyltransferase forms are found in a majority of the population. These enzymes play an important role in the metabolism of various drugs, for example isoniazid, which is used to combat tuberculosis. Probably, tests will be available in the near future to determine patient’s genotypes for metabolic conversion, i.e. whether they are fast or slow metabolizers.

Pharmacogenetic effects can be caused by differences in enzymatic conversion rates, but also by inter-individual variations in the proteins to which the drugs are targeted (target proteins), or by genetically determined unintended interference with normal physiological processes. For example, asthma drugs such as salbutamol attach them themselves to a particular receptor. Genetic differences in this receptor mean that the efficacy of such drugs varies from patient to patient. Interference by genetically determined factors can, for example, occur with anti-malarial drugs, which may result in serious forms of anaemia.

The development of pharmacogenetics began in the 1950s. Today, the discipline is the focus of increasing attention for various reasons. Considerable momentum is obtained from the rapid expansion of scientific knowledge regarding the human genome, which has shed light on genetically determined factors affecting the action of drugs. In addition, ever more epidemiological data is available on the incidence of side effects of drugs. Meta-analyses indicate that serious side effects are more common, even with correctly prescribed medicines, than was until recently supposed. Data from the USA suggests that 7 per cent of hospital patients receiving medication experience serious side effects. Although such problems are not attributable to genetic factors alone, the application of pharmacogenetic principles could reduce their incidence.

Interest in pharmacogenetics has also been fuelled by the increasing emphasis on efficiency in health care. By taking more account of individual genetic make-up, better use can be made of medicines. In the future, the dosages prescribed for individual patients may in certain cases be adjusted on the basis of DNA test results, thereby hastening recovery and reducing side effects. A more rapid recovery is, for example, possible if the metabolic conversion rate is known when antidepressants or antipsychotics are initially administered. Furthermore, pharmacogenetic information about individual sensitivity would reduce the incidence of side effects when antidepressants, antipsychotics and other medicines, such as anti-tumour drugs, are prescribed. Cost-savings are therefore possible, especially where hospital admissions can be prevented. However, savings in drug costs are unlikely, as an increased dose may be just as desirable as a decreased dose.

Pharmacogenetic information is potentially significant in relation to insurance and employment. DNA tests could indicate, for example, that an individual was more likely to become ill and thus to incur expenses for the insurer/employer. It is open to question whether the Medical Examinations Act provides sufficient clarity regarding the use of genetic data, or to what extent the provisions of the Act are adhered to in practice. The developments outlined above require revision of the regulations on DNA testing (presently confined to special clinical genetics centres).

As pharmacogenetic knowledge develops, it can be increasingly used for the development of new medicines. This may result, on the one hand, in drugs that exhibit less variation in their metabolic conversion rates and, on the other, in drugs for which pre-prescription DNA or enzyme testing is desirable. Most recently released drugs have been developed with metabolic variations involving the main cytochrome P-450 enzymes in mind. In the years ahead, the number of potential pharmaceutical research topics will grow rapidly as a result of increasing (pharmaco-) genetic knowledge (in the literature, this research area is generally referred to as pharmacogenomics). This is likely to lead to the development of many more pharmaceutical products. In turn, the availability of new drugs will have implications for the health budget and necessitate greater emphasis on the efficacy of the products prescribed.

Where pharmacogenetic tests are carried out, it is important that the individuals concerned are properly informed, partly because misapprehensions regarding genetic testing are commonplace. The purpose and scope of such tests should be made clear and steps taken to ensure the confidentiality of the results obtained. These principles apply equally to (pharmaco-) genetic scientific research into associations between genotypes and the effects of drugs or the prevalence/risk of disease. In that case, allowance should also be made for the fact that the implications of such research are not always entirely clear. Furthermore, interpretations by researchers may in a later stage shown to be wrong. The advisability of informing the patients concerned about scientific research findings therefore warrants careful consideration.