Description
Introduction
Multiple variables influence the selection and optimization of drug therapy for each individual patient. Pharmacogenomics, the study of the influence of individual genetic variations on drug response in patients, may yield additional information to further enhance safe and effective medication use.
Whereas the field originally focused on the effects of specific variants within individual genes on drug response (i.e., pharmacogenetics), efforts increasingly examine the role of multiple variants across the genome and their potential relationship to drug therapy outcomes.
As our understanding of pharmacogenomics and the biological relevance of specific genetic variants in individuals’ drug metabolizing enzymes, drug transporter proteins, and drug target receptors to certain drug responses has increased, we have learned that multiple variations across the genome can contribute to significant and relatively predictable treatment outcomes. Virtually every therapeutic area involving medication use includes a drug for which documented genetic variability has the potential to affect drug response. Some of this information is included in the FDA-approved package insert prescribing information. For some agents, the suitability of a specific drug or the determination of an appropriate initial dose for an individual patient based on pharmacogenetic information has been incorporated into dosing algorithms and patient care. As such, it is essential that health care professionals can interpret and utilize this information to facilitate safer and more effective use of medications for individual patients.
Genetic Variation within the Human Genome
The human genome is comprised of approximately 3 billion nucleotide base pair sequences that encode for molecular DNA with, except for identical twins, each individual having his/her own unique human genome sequence. Four nucleotide bases (adenine, guanine, cytosine, and thymine) are responsible for constituting the sequence of each single strand of DNA. Variations in nucleotide sequences can occur, and contribute to alterations in the expression and activities of certain genes.
The location of these variations within a DNA sequence on a particular chromosome can have a profound impact on the ultimate biological activity or characteristic of that gene or lead to little or unknown consequences.
Proteins are involved in most enzymatic, structural, and biologic functions associated with drug disposition and effects. The processes involved in DNA replication, RNA transcription, and translation to synthesized proteins are complex. Each of these processes is potentially susceptible to consequences of DNA sequence variations.
Genetic variations can take many forms, including single nucleotide base substitutions (e.g., a cytosine substituted for an adenine), insertions or deletions of a nucleotide base within a sequence, and deletions or extra copies of entire DNA sequences. Variations in DNA that occur at a frequency of greater than 1% in the population are called polymorphisms. The most common genetic variations in humans are referred to as single nucleotide polymorphisms (SNPs) and result from the substitution of one nucleotide base for another. The specific location of a SNP within a gene is important. As mentioned previously, genetic variations can be of unknown or no clinical consequence or they can lead to a truncated, dysfunctional, or complete lack of protein product that is associated with an alteration in drug response.
Clinical Significance of Genetic Polymorphisms
SNPs and other genetic variations influence drug response at different levels through alterations in the activities of enzymes or proteins involved in drug absorption, transport, metabolism, elimination, or at the drug target receptor (site of drug action). Clinically relevant polymorphisms have been identified for genes that encode for most of the common enzymes involved in drug metabolism. Most enzymes 10 DAVIS’S
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are localized intracellularly throughout a wide variety of tissues in the body, including the enterocytes that line the intestine and within hepatocytes. Variants that cause diminished or absent enzyme activity decrease drug metabolism processes. In this case, if the drug is metabolized to an inactive product, then the prolonged persistence of the parent drug in the body could result in excessive pharmacologic effects and potential toxicities may occur. If the drug requires enzymatic conversion to a pharmacologically active metabolite, drug response may be reduced or absent. In contrast, if the variation is due to extra copies of a gene that results in increased enzymatic activity, opposite effects on drug metabolism and response can occur.
Similar outcomes can be associated with polymorphisms in genes that encode for membrane transporter proteins that are responsible for drug transport into cells (influx), as well as proteins that participate in energy-dependent processes that export drugs out of cells (efflux transporters).
Polymorphisms in drug transport proteins can influence drug response by altering drug gastrointestinal absorption, uptake and distribution in tissues, exposure to intracellular drug metabolizing enzymes, and elimination via the bile or urine. Finally, some genes that encode for certain drug receptors are highly polymorphic, resulting in attenuated or exaggerated drug responses.
The number of polymorphic genes responsible for variations in drug response at drug receptors is relatively small compared to those associated with drug metabolizing enzymes or transport proteins; however, this area has undergone the least amount of study to date.