Current Pharmaceutical Design - Volume 16, Issue 2, 2010

Long before the term pharmacogenetics was coined, it was recognized that patients respond very differently to treatment with a drug. Indeed, the question how variability of drug response can be explained is as old as the science of pharmacology. The concept of interindividual differences in drug response was proposed as early as 1909 by Garrod in his book The Inborn Errors of Metabolism [1]. Only since the late 50s of the l Read More

More than fifty years of pharmacogenetic research have produced many examples of the impact of inherited variability in the response to psychotropic drugs. These successes, however, have as yet failed to translate into broadly applicable strategies for the improvement of individual drug treatment in psychiatry. One important argument against the widespread adoption of pharmacogenetics as a clinical tool is the lac Read More

Thiopurines are widely used in the treatment of inflammatory bowel disease (IBD). However, in clinical practice azathioprine (AZA) or 6-mercaptopurine (6-MP) are not effective in one-third of patients and up to one-fifth of patients discontinue thiopurine therapy due to adverse reactions. The observed interindividual differences in therapeutic response and toxicity to thiopurines are explained to a large extent by Read More

Pharmacogenetics is a rapidly developing field, especially in oncology. In the most ideal situation pharmacogenetics will allow oncologists to individualize therapy based on patients’ individual germline genetic test results. This can help to improve efficacy, reduce toxicity and predict non-responders in a way that alternative therapy can be chosen or individual dose adjustments can be made. Multiple pathways have been s Read More

Over the last decades important progress is being made regarding disease modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). Nevertheless, a substantial part of the patients fail to achieve a good response and/or experience toxicity, which limits further treatment leading to progression of inflammation and destruction of joints. These high interindividual differences in drug respons Read More

Patient variability in clinical response to the calcineurin inhibitors (CNIs) cyclosporine A and tacrolimus partly results from differences in CNI exposure. For tacrolimus drug interactions and genetic variability relate to tacrolimus exposure. Patients carrying the CYP3A5*1 allele have an increased tacrolimus metabolism, hence lower drug exposure. Adjusting the tacrolimus dose to this genotype is a tool to optimize thera Read More

The identification of the genes encoding CYP2C9, the principal metabolizing enzyme of the coumarins, and VKORC1, the molecular target for coumarins, has strongly stimulated the research on pharmacogenetics of vitamin K antagonists, also designated as coumarins. From 1999 to 2004 a number of observational studies firmly established associations between being carrier of the CYP2C9*2 and especially the CYP2C9*3 al Read More

Genetic variation in the receptors and other intracellular targets that mediate the pharmacodynamic effects of drugs can affect therapeutic outcomes. However, at present greater knowledge is available concerning the extent of gene variation in drug metabolizing enzymes that determine drug pharmacokinetics and, in turn, drug efficacy and toxicity. Information on the incidence of polymorphisms in the cytochro Read More

During the last decade, a greater focus has been given to impact of genetic variation in membrane transporters on the pharmacokinetics and toxicity of numerous therapeutic drugs. While the majority of transporter-related pharmacogenetic research has been in regards to classic genes encoding the outward-directed ATP-binding cassette (ABC) transporters, such as ABCB1 (Pglycoprotein), ABCC2 (MRP2), and ABCG2 (BC Read More

With the exponential increase in publications on DNA markers explaining and/or predicting response to drug therapy, the potential of pharmacogenetic testing of individual patients to optimize drug treatment is expanding. For the identification of pharmacogenetic markers, several techniques can be used. The specific method usually depends on the requirements of the study, ranging from determining one or two si Read More

The detailed knowledge of the human genome has not fulfilled its promise as yet. It seems fair to say that we are far from treating existing diseases by therapeutic interventions developed on the basis of genetic knowledge. However, pharmacogenetics has shown to be useful in improving our understanding of pharmacotherapy. Industry is starting to embed this knowledge in the design of innovative drugs and th Read More

In genomics research, pathways that lead to disease and the role of drugs in these pathways are being unravelled at a high rate. In this paper ethical and social challenges related to pharmacogenomics research are discussed as well as clinical applications. In research, ethical thinking evolves due to the fast pace of research. Genome-wide association studies trying to identify genes that contribute a small risk to comm Read More