Current Pharmacogenomics - Volume 1, Issue 3, 2003

After more than 50 years of investigations, pharmacogenetic efforts have crystallized in several findings relating genetically determined pharmacokinetic and pharmacodynamic factors to treatment response. Metabolic enzymes and neurotransmitter proteins contain genetic polymorphisms that alter their interaction with psychotropic drugs and contribute to response variability. This knowledge can be used to predict clinical results and adverse reactions. Current clinical applications include rapid methods for the characterisation of metabolic status that is used in clinical trials for the identification of individuals susceptible to side-effects. This practice is being extended to clinical laboratories to avoid toxic reactions to specific treatments. Pharmacogenetics methods for the pre-treatment prediction of clinical response to the antipsychotic drugs clozapine, risperidone, olanzapine and haloperidol are in development and expected to be available for clinical use in the next decade. However, much is still expected from the wealth of information produced by pharmacogenomic research. Pharmacogenomic strategies, including large scale functional studies in brain areas related to the aetiology of mental disorders, will increase the knowledge on therapeutic mechanisms and identify novel targets. Pharmacogenomic advances will be translated into more specific and safer drugs and tailoring of drug prescription according to the patient's genetic susceptibilities. Pharmacogenetic and pharmacogenomic investigations have the potential to transform psychiatric treatment in the next decades.

Cytochromes P450 (CYPs) are multifunctional enzymes that are active in the oxidative metabolism of many drugs and play a dominant role in the elimination of drugs from the body. Pharmacokinetic interactions may arise when the biotransformation and elimination of a drug are impaired by coadministered drugs. Thus, drugs may compete for biotransformation by a common CYP. Adverse drug reactions, including toxicity, can occur if elimination is dependent on a CYP that exhibits defective gene variants. Thus, the genetic makeup of the individual is a major influence on the duration of drug action, as well as drug efficacy and safety. This review summarises recent information on the mechanisms of drug-drug interactions that are due to impaired CYP function and also outlines the impact of aberrant CYP genes on drug biotransformation. Evidence is presented that CYP pharmacogenetics affects the propensity for certain drug-drug interactions. Thus, the future safe use of drug combinations in patients may require genotyping and phenotyping of individuals before the commencement of therapy. Identification of subjects who metabolise drugs in a different fashion from the general population should minimise the impact of pharmacogenetic variation on drug pharmacokinetics.

The capacity to repair damaged DNA is a basic tool by which the mammalian cell maintains its genetic integrity and prevents neoplasm; however, DNA repair function could be modified by genetic polymorphisms. Recent molecular epidemiological studies have indicated that these genetic variants occur in the normal population and can be used to predict individual cancer risk. Since variation in the function of these genes might impact a cancer cell's viability or resistance to treatment, genetic variants in DNA repair might act as a valuable marker in forecasting the results of cancer treatment. This possibility has been outlined by some clinical pilot studies of genetic polymorphisms in the DNA repair genes. With the biological importance of the DNA repair genes, studies of these genetic variants occurring in the general population will further our understanding of cancer etiology and behavior.

Recent sweeping advances in technology have driven a transformation in the science of pharmacogenetics. Understanding this transformation informs the future direction of the field. Generation of high density SNP and LD maps following quickly on the heels of sequencing of the human genome combining with great advances in bioinformatics have opened the door for application of candidate gene and genome-wide approaches to understanding both drug efficacy and adverse events at the DNA level. A future in which pharmacogenetics will play a critical role in drug development and clinical practice requires that we meet today's challenges. These challenges include establishing fluent dialog between pharmaceutical companies and regulatory agencies, achieving meaningful standardization of technical aspects of these new methodologies, bringing precision to the language of pharmacogenetics to provide clarity for public policy debates and realizing education goals to bring the knowledge and power of pharmacogenetic analyses to clinical practice.

Only 50-75% of patients are estimated to benefit from successful drugs. Pharmacogenetics research has demonstrated that the risk of therapeutic failure, drug toxicity and drug interactions is not the same for everyone and that genetic variation is an important determinant of these events. With the maturation of the Human Genome Project, a rational approach to new and better therapies is now viewed as a realistic prospect that will result in drugs personalized to small, genetically defined groups of patients or even to individuals. If treatment is guided by genetic profiles individualized to specific drugs, we expect to reduce the frequency and severity of adverse drug reactions. A large set of genetically polymorphic markers predictive of human drug response is now available. Foremost among these markers is the family of pharmacokinetic polymorphisms mainly consisting of the polymorphic human drug metabolizing enzymes. So far, clinical application of this new knowledge has been limited. In this commentary, we describe the Marshfield program in personalized medicine now under way in Wisconsin, and the United States Patient Safety Initiative as the first two attempts to apply pharmacogenetics to improve pharmaceutical intervention in human disease in the United States in large patient populations.

A major goal of the Human Genome Project is to establish “personalized medicine” on the basis of individual genetic variations. Among the genetic differences present in human populations, polymorphisms in genes that encode various enzymes, transporters, and receptors involved in the metabolism of drugs are considered to be medically important because some can affect therapeutic efficacy of drugs and / or adverse reactions. We have been conducting extensive screening programs to detect genetic variations in the Japanese population. In particular, we seek single-nucleotide polymorphisms (SNPs) in genes of interest by combining direct DNA sequencing with computational analysis. These efforts have allowed us to construct comprehensive SNP maps of 214 gene loci that contain a total of 6845 variations. In this review, we introduce the molecular features of each of those loci, such as regional distributions of SNPs, non-synonymous substitutions, insertion / deletion polymorphisms within coding regions, and other types of variation. This directory for human variations should provide a fundamental molecular basis for understanding the pharmacokinetics or pharmacodynamics of drugs used to treat individual patients.