AboutDr Alan Galbraith Expertise I can answer most questions on most drugs. Answers can be given in either technical or layperson terminology. My main areas of interest are psychiatric, gastrointestinal and cardiovascular drugs.
Experience I have been a university lecturer/head of department for almost thirty years, but am now retired. My research interests were alcohol, smoking and cardiovascular disease.
Organizations Institute of Biology, London.
Publications Author of "Fundamentals of Pharmacology" 5th Edition published in November 2007 by Pearson Education, Australia.
Question Using CYP2D6 as an example, explain what is meant by genetic polymorphism of drug metabolising enzymes
Can you please help me with this as I have had no luck in finding this in pharmacology books or on the internet.
Your help will be appreciated.
Thanks
Answer Dear Craig
I have written a summary of genetic polymorphism in general
rather than use a specific example of a cytochrome P450 enzyme. I hope this is acceptable to you as I feel to use one of the P450 variants it would be to involved.
Our genes are responsible for the coding of enzymes,
receptors, ion channels, drug transporter molecules and
other physiological systems involved in observable drug
responses. Some of these proteins are located at the drug's
site of action, while others are involved in the metabolism
of drugs.Within the human population genetic variation
causes individuals to express different forms of these
proteins. This phenomenon is known as genetic polymorphism.
Genetic polymorphism occurs when a genetic
trait (e.g. coding for the synthesis of a particular enzyme)can be expressed within the population in two (or more)different forms, or phenotypes. It is this type of polymorphism which can lead to differential drug responses.
In pharmacogenetics, genetic polymorphism is most
widely studied in relation to drug metabolism. More than
20 human enzymes associated with drug metabolism have
polymorphisms. In addition, ethnicity plays a role in the
frequency of these polymorphisms.
A number of important enzymes are involved in
drug metabolism—N-acetyltransferase and some of the
cytochrome P450 family of oxidative enzymes. For these
enzymes, human populations can be divided into two
groups based on their ability to metabolise particular
drugs: responders (extensive metabolisers) and nonresponders(poor metabolisers).
From a clinical perspective, non-responders are of great
importance. If, during therapy, plasma drug concentrations
remain high because of an inability to degrade the active
agent, non-responders are at risk of developing serious
adverse drug reactions. Such individuals may require a
reassessment of the dose regimen or choice of drug
in order to avoid toxicity. For the responders, the worst
scenario is that the drug will be less effective because the plasma concentration is subtherapeutic. This again could be redressed by altering the choice of drug or dosage.
