Pharmacogenetics

Pharmacogenetics is the study of how people respond to drug therapy. Through research and multiple studies, it has been confirmed that individuals often respond differently to the same drug therapy. This is typically due to one’s genetic makeup, but overall health, diet, and environmental factors also play a significant role in how a person responds to medication.

The drug disposition process is a complex set of physiological reactions that begin immediately once the drug is administered. As a drug is administered, it is absorbed and distributed to the targeted areas of the body. It interacts with cellular components, such as receptors and enzymes, that further metabolize and breakdown the drug. Eventually, the drug will be excreted from the body.

During this process, genetic variation may alter the therapeutic response of an individual and potentially cause an adverse drug reaction (ADR). Approximately, 20 to 95 percent of variations in drug disposition, such as ADRs, can be attributed to genetic variation.

Sensitivity to both dose-dependent and dose-independent ADRs can have roots in genetic variation. Individuals’ susceptibilities to ADRs, are connected to Polymorphisms in kinetic and dynamic factors, such as cytochrome P450 and specific drug targets. Although the characteristics of the ADR dictate the true impact and significance of these factors, in most cases, multiple genes are involved . 

Further studies and future analyses using genome-wide SNP profiling could provide a technique for assessing several genetic susceptibility factors for ADRs as well as identifying their joint effects. One of the main challenges to the study of the relationship between genetic variation and ADRs is an inadequate number of patient samples. In order to resolve this issue, Pirmohamed and Park have proposed that prospective randomized controlled clinical trials become a part of standardized practice to ultimately prove the clinical utility of genotyping all patients as a means to prevent ADRs.

As we review some of the current work in pharmacogenetics we can identify what might be expected to come from more rigorous studies on the interaction between social, behavioral, and genetic factors. Researchers have given several well-established examples of differences in individual drug response that are due to genetic variations in a variety of cellular drug disposition machinery. One example is the drug transporters or enzymes responsible for drug metabolism. For instance:

  • With the knowledge that the HER2 gene is overexpressed in approximately one fourth of breast cancer cases, researchers developed a humanized monoclonal antibody against the HER2 receptor in hopes of inhibiting the tumor growth associated with the receptor. Genotyping advanced breast cancer patients to identify those with tumors that overexpress the HER2 receptor has produced promising results in improving the clinical outcomes for these breast cancer patients (Cobleigh et al., 1999).
  • A therapeutic class of drugs called thiopurines is used as part of the treatment regimen for childhood acute lymphoblastic leukemia. One in 300 Caucasians has a genetic variation that results in low or nonexistent levels of thiopurine methyltransferase (TPMT), an enzyme that is responsible for the metabolism of the thiopurine drugs. If patients with this genetic variation are given thiopurines, the drug accumulates to toxic levels in their body causing life-threatening myelosuppression. Assessing the TPMT phenotype and genotype of the patient can be used to determine the individualized dosage of the drug (Armstrong et al., 2004).
  • The family of liver enzymes called cytochrome P450s plays a major role in the metabolism of as many as 40 different types of drugs. Genetic variants in these enzymes may diminish their ability to effectively break down certain drugs, thus creating the potential for overdose in patients with less active or inactive forms of the cytochrome P450 enzyme. Varying levels of reduced cytochrome P450 activity is also a concern for patients taking multiple drugs that may interact if they are not properly metabolized by well-functioning enzymes. Strategies to evaluate the activity level of cytochrome P450 enzymes have been devised and are valuable in planning and monitoring successful drug therapy. Some pharmaceutical drug trials are now incorporating early tests that evaluate the ability of differing forms of cytochrome P450 to metabolize the new drug compound (Obach et al., 2006).

Some pharmacogenetics research has focused on the treatment of psychiatric disorders. Pharmacological treatment of many psychiatric disorders changed drastically due to the introduction of a new class of drugs known as selective serotonin reuptake inhibitors (SSRIs). SSRIs offer significant improvements over the previous generation of treatments, including improved efficacy and tolerance for many patients. However, some patients have not responded well to SSRI treatments and have experienced ADRs.

New pharmacogenetic studies have found that these ADRs may be the result of genetic variations in serotonin transporter genes and cytochrome P450 genes. Additional studies and replication of these findings are necessary to expand knowledge of ADRs. It would be possible to screen and monitor patients using genotyping techniques to create individualized drug therapies if the characterization of the genetic variations is completed and is fully understood.

One of the most significant challenges to the development of individualized drug therapies is the often polygenic or multifactorial inherited component of drug responses. Isolating the polygenic determinants of the drug responses is a difficult and lengthy task. However, a good understanding of the drug’s mechanism of action and metabolic and disposition pathways should be the basis of all investigations. This knowledge can help assist in directing genome-wide searches for gene variations associated with drug effects as well as candidate-gene approaches of investigation. 

Additionally, proteomic and gene-expression profiling studies are also valuable ways to provide evidence and understand the pathways by which the gene of interest operates to affect the individual’s response to the drug. However, it is difficult to show an association. The characterization of the underlying biological mechanisms is an essential component of moving genetic findings into the area of risk reduction. Another primary aspect of utilizing genetics to improve prevention and reduce disease is an understanding of the distribution of the genetic variations in the patients being treated.

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