Pharmacogenomics - What's New in Pharmacogenomics?
Pharmacogenomics - What's New in Pharmacogenomics?
The last few years have witnessed an unprecedented revolution in the biologic sciences. The most publicized aspect of this phenomenon is the Human Genome Project -- with good cause. The technologies that have been developed and the discoveries that are being made as a result of the Human Genome Project will change both future drug development and the practice of medicine as we know it today. Recent developments and applications of genomic techniques have transformed the way pharmacologists view the impact of the patient's genetic make-up on drug efficacy. Stratifying patients based on their genotypic profile may lead to selection of medications to maximize therapeutic effect while at the same time reducing significant drug side effects. Additionally, the ability to decipher one's genetic make-up will have a significant impact on medical diagnosis and may lead to earlier detection of diseases such as cancer.
For many years, pharmacologists have been using statistics and genetic tools to investigate inheritability of drug metabolism. Pharmacogenetics, as it was called then, was an indirect way of looking at the impact of genes on pharmacology and therapeutics based on observing associations between drug efficacy and easily measurable phenotypic traits in families. The first appearance of this in MEDLINE dates back to a German publication from 1964. However, the technologies used in that and subsequent papers were limited, and pharmacogenetic analysis was restricted to drawing conclusions only when discrete and large inherited effects, mainly on toxicity, were easily recognized. For instance, one of the oldest examples of pharmacogenetics (even before the term was coined) is the toxic neuritis that appeared in patients who were slow isoniazid acetylators, discovered in 1953. During the 1990s, the genomic revolution has driven technologic improvements that have dramatically increased the utility of this approach, enabling pharmacologists now to search for direct relationships between changes in genes and the pharmacology of a particular drug. The ability to relate the changes in drug response to either inherited or spontaneously arising genetic changes rather than associated phenotypes is called pharmacogenomics. These techniques have been developed to the point that we are now able to look at discrete (ie, presence or absence of a trait) as well as continuous (ie, variations in protein levels) effects of genes on drug metabolism, in terms of efficacy as well as toxicity.
A good example of the evolution of the technologies and their application can be demonstrated by reviewing the literature about thiopurine methyltransferase (TPMT). TPMT is a genetically polymorphic enzyme that catalyzes the S-methylation of thiopurine drugs, such as 6-mercaptopurine, and is primarily responsible for the metabolism of this class of drug. A study by Weinshilboum and Sladeck documents the inherited toxicity linked to a homozygous trait resulting in very low or absent enzyme activity. The most recent publication by Weinshilboum and other colleagues focused on efficacy, demonstrating the relationship between TPMT gene polymorphisms and the level of red blood cell TPMT activity. The findings in this article emphasize the importance of determining the patient's TPMT genotype before administering 6-mecaptopurine therapy and point out, for example, that some people should probably receive higher doses of 6-mercaptopurine to be effectively treated.
Most of the publications in pharmacogenetics have dealt with pharmacokinetic examples of the impact of human genetic changes on drug metabolism. In general, the findings have shown that when drugs are not efficiently metabolized, most often due to polymorphisms affecting the cytochrome P450 system, they can accumulate and result in toxicity. Reviews in pharmacogenomics have been published; however, there are still relatively few original articles exploring the relationship between genetic polymorphisms that alter drug targets and activity of the drug. To better understand the relationship between genetics and pharmacodynamics, it can be useful to differentiate between recessive and dominant manifestations of efficacy and/or toxicity. Surveying the literature from this point of view reveals that almost all the publications in pharmacogenomics are examples of "recessive loss of efficacy," which means that a small proportion of homozygous patients for a trait (mainly a single nucleotide pair [SNP]) are not effectively treated with the drug.
The last few years have witnessed an unprecedented revolution in the biologic sciences. The most publicized aspect of this phenomenon is the Human Genome Project -- with good cause. The technologies that have been developed and the discoveries that are being made as a result of the Human Genome Project will change both future drug development and the practice of medicine as we know it today. Recent developments and applications of genomic techniques have transformed the way pharmacologists view the impact of the patient's genetic make-up on drug efficacy. Stratifying patients based on their genotypic profile may lead to selection of medications to maximize therapeutic effect while at the same time reducing significant drug side effects. Additionally, the ability to decipher one's genetic make-up will have a significant impact on medical diagnosis and may lead to earlier detection of diseases such as cancer.
For many years, pharmacologists have been using statistics and genetic tools to investigate inheritability of drug metabolism. Pharmacogenetics, as it was called then, was an indirect way of looking at the impact of genes on pharmacology and therapeutics based on observing associations between drug efficacy and easily measurable phenotypic traits in families. The first appearance of this in MEDLINE dates back to a German publication from 1964. However, the technologies used in that and subsequent papers were limited, and pharmacogenetic analysis was restricted to drawing conclusions only when discrete and large inherited effects, mainly on toxicity, were easily recognized. For instance, one of the oldest examples of pharmacogenetics (even before the term was coined) is the toxic neuritis that appeared in patients who were slow isoniazid acetylators, discovered in 1953. During the 1990s, the genomic revolution has driven technologic improvements that have dramatically increased the utility of this approach, enabling pharmacologists now to search for direct relationships between changes in genes and the pharmacology of a particular drug. The ability to relate the changes in drug response to either inherited or spontaneously arising genetic changes rather than associated phenotypes is called pharmacogenomics. These techniques have been developed to the point that we are now able to look at discrete (ie, presence or absence of a trait) as well as continuous (ie, variations in protein levels) effects of genes on drug metabolism, in terms of efficacy as well as toxicity.
A good example of the evolution of the technologies and their application can be demonstrated by reviewing the literature about thiopurine methyltransferase (TPMT). TPMT is a genetically polymorphic enzyme that catalyzes the S-methylation of thiopurine drugs, such as 6-mercaptopurine, and is primarily responsible for the metabolism of this class of drug. A study by Weinshilboum and Sladeck documents the inherited toxicity linked to a homozygous trait resulting in very low or absent enzyme activity. The most recent publication by Weinshilboum and other colleagues focused on efficacy, demonstrating the relationship between TPMT gene polymorphisms and the level of red blood cell TPMT activity. The findings in this article emphasize the importance of determining the patient's TPMT genotype before administering 6-mecaptopurine therapy and point out, for example, that some people should probably receive higher doses of 6-mercaptopurine to be effectively treated.
Most of the publications in pharmacogenetics have dealt with pharmacokinetic examples of the impact of human genetic changes on drug metabolism. In general, the findings have shown that when drugs are not efficiently metabolized, most often due to polymorphisms affecting the cytochrome P450 system, they can accumulate and result in toxicity. Reviews in pharmacogenomics have been published; however, there are still relatively few original articles exploring the relationship between genetic polymorphisms that alter drug targets and activity of the drug. To better understand the relationship between genetics and pharmacodynamics, it can be useful to differentiate between recessive and dominant manifestations of efficacy and/or toxicity. Surveying the literature from this point of view reveals that almost all the publications in pharmacogenomics are examples of "recessive loss of efficacy," which means that a small proportion of homozygous patients for a trait (mainly a single nucleotide pair [SNP]) are not effectively treated with the drug.
