Mapping Humanity by Joshua Z. Rappoport PhD

Author:Joshua Z. Rappoport, PhD
Language: eng
Format: epub
ISBN: 9781950665259
Publisher: BenBella Books, Inc.
Published: 2020-05-05T00:00:00+00:00

PHARMACOKINETICS

Much of the research in the area of pharmacogenomics focuses on the general field of pharmacokinetics, which essentially concerns the different aspects of drug function besides the actual mode of action for the medicinal effect. In general, pharmacokinetics is described by the acronym ADME (absorption, distribution, metabolism, and excretion). Any variations in genes that encode proteins that play a role in any of these steps can result in differences in the pharmacokinetics of a particular drug in an individual. These could include enzymes involved in the activation or breakdown of a drug, or transporters that move the drug between two cellular compartments.

When considering the potential effect of any drug, pharmacokinetics is generally combined with the concept of pharmacodynamics. Pharmacodynamics is defined by the actual mode of action of the drug—what it actually does on a molecular level; for example, an inhibitor blocks the function of a particular enzyme. Pharmacodynamics can certainly be altered by individual genomic variation. You can picture an enzyme inhibitor that must fit into the target enzyme as a cork going into a bottle, and thereby preventing any wine from spilling out. But what if your particular bottle is a smaller size, and the cork won’t fit? An analogous inhibitor would be unable to stop the normal function of the enzyme because of a specific structural difference in the target resulting from genetic variation.

In some cases, as with codeine, people with reduced function of enzymes involved in drug activation simply cannot feel the benefits of that medicine. In other cases, certain genetic variants can cause significant toxicity when a person is treated with a specific drug. The drug 6-mercaptopurine (6-MP) is an immunosuppressant classically prescribed as frontline therapy in autoimmune conditions such as Crohn’s disease—a type of inflammatory bowel disease. The enzyme thiopurine S-methyltransferase inactivates 6-MP and is required to maintain a functional, but nontoxic, level of 6-MP in the body. This is like running water into a bath with the drain open so that some water remains but the bath doesn’t overflow; whereas if the drain is plugged, the bath will overflow eventually. A small percentage of people have reduced function of this enzyme. In these individuals the 6-MP can build up and cause significant toxicity, so it is standard practice to ensure that a patient has sufficient thiopurine S-methyltransferase before prescribing 6-MP. The standard approach to doing this involves specific enzyme activity testing in a dedicated biochemistry laboratory. Alternatively, by sequencing the gene encoding thiopurine S-methyltransferase, any variants that might alter function can be detected.

The ultimate promise of pharmacogenomics is that an individual’s genomic DNA sequence can be analyzed for mutations that could be relevant to any treatments that person might ever receive. Rather than incremental evaluations for enzyme activity, or analysis of individual gene sequences, all that would need to occur would be a comparison of the person’s genome with known variants associated with particular drug interactions.

The potential utility of pharmacogenomics is limited only by the known connections between specific gene variants and particular drugs.

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