Drug Metabolism:
Something Else To Consider

A frustration in the hope of eradicating cancer is that patients respond very differently to treatments, even among those with apparently similar cancers. In addition to needing to tailor a therapy to the genetics of the tumor and/or its environment, researchers now realize that there are significant differences in the way people metabolize drugs.

Improving Dosing and Decreasing Adverse Events

Genetic variants in drug metabolizing enzymes can have a significant effect on the way a person responds to a drug. They can speed up or slow down enzymatic activity, or even inactivate an enzyme.

In some patients, known as rapid metabolizers, drugs are metabolized too quickly. As a result, the average dose of the drug may be broken down too quickly to be effective, and a higher dose may be needed.

In slow metabolizers, a drug administered at the recommended dose can accumulate due to such slow metabolism, potentially reaching toxic levels in the patient's system and leading to adverse reactions. Such patients may require a smaller dose.

In conjunction with other factors, pharmacogenomics offers the potential to enable doctors to identify the patients who are rapid or slow metabolizers of certain drugs and to adjust dosing accordingly to achieve both effective and safe treatment.

	Rapid metabolizers may break down a drug too quickly and require higher doses. Slow metabolizers may build up toxic levels of the drug and require smaller doses.
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More specifically, the active agents in some drugs given to patients may never end up being present in people who do not metabolize the drug in the expected way.

• These differences could also account for the wide range of side effects different people experience when they take identical drugs.

Considerable research, called pharmacogenomics, is now being directed to help understanding these processes.

Pharmacogenomics – more about this in the ‘OMICS’ section

Pharmacogenomics is the study of how genes affect a person's response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person's genetic makeup.

Many drugs that are currently available are "one size fits all," but they don't work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions).

Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body's response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions.

The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.

Pharmacogenomic research - Studies have found that the chemotherapy drugs:

• Gefitinib (Iressa) and erlotinib (Tarceva), work much better in lung cancer patients whose tumors have a certain genetic change.
• Cetuximab (Erbitux) and panitumumab (Vecitibix) do not work as well in the 40 percent of colon cancer patients whose tumors have a particular genetic change.

Genetic Variation (polymorphisms - SNPS)

Genetic variation (polymorphisms-SNPS) accounts for some of the variability in the how different people respond to the same drug.

For example:

With N-acetyltransferases, individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly (split roughly 50 / 50 in the population of Canada). This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity.

 

A Few More Terms

Pharmacokinetics (meaning the study of time dependency, sometimes abbreviated as "PK") is a branch of pharmacology dedicated to the determination of how a drug administered to a person is processed, and specifically, how long does it stay in the body.

		This is important in determining a correct dose, as we need enough drug in our bodies to do the job but not enough to become toxic. This is why chemo is given in cycles and why some people need a "chemo holiday" to give the chemo time to get out of their body if their side effects begin to build up.
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Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug. A drug's pharmacodynamics can be affected by physiologic changes due to: aging, other drug interactions and genetic mutations.

To administer correct drug doses, it is important to know:

• How well / quickly the liver metabolizes the administered drug (this is specific to individuals).
• Drug distribution: When a drug is introduced into the body where does it ends up.
• Protein Binding: Most drugs bind to proteins. It is important to understand how much of a given drug binds to protein as that determines how much is available in the body (more binding - less drug).
• People who participate in "pharmacokinetic studies" are asked to provide blood or urine samples at many different intervals following the administration of drugs. While this may seem excessive, it is the only way for scientists to determine how the drug is metabolized and individual variation in the metabolism of the drug.

CISN Summary

• Pharmacokinetics is the study of what the body does to a drug.
  • The strategy for treating patients with drugs is to give sufficient amounts that the required theraputic effect arises, but not a toxic dose.
• Pharmacodynamics is the study of what a drug does to the body.
• Before a drug can be effective, it must be absorbed and distributed throughout the body. It is important to know how medications are absorbed into the body, what happens when the medications are there, and how your body gets rid of them.
• Advocate for more research in the field of pharmacogenomics so that routine pharmacogenomic testing will some day be incorporated into drug dose determinations to decrease over-and-under treating patients.

  In today’s oncology clinic we routinely do a complete blood count to insure that patients have an adequate amount of platelets, red and white blood cells prior to administration of chemo; this has become standard of care. We do not yet know enough about an individual’s pharmacogenomic makeup to tailor their drug dose.