Wednesday, 16 May 2012

The future of pharmacy and medicine?


The future of pharmacy and medicine? by Bjarn Biederstadt

In recent years there is a new science emerging called pharmacogenomics. Pharmacogenomics is defined as “Looking for genetic differences within a population that explain certain observed responses to a drug or susceptibility to a health problem” (Barlow-Stewart & Saleh 2007). There are many benefits of pharmacogenomics such as prescribing drugs at far more accurate dosages through the use of a individual’s genome, rather than using tools such as body weight and/or age, drug design/development to maximise the therapeutic effects but cause less damage to healthy cells and vaccine development by genetic screening a population, information would be made available to select people for clinical trials and exclude people from trials because the drug in question could be harmful or possibly ineffective (Barlow-Stewart & Saleh 2007). There are two goals within pharmacogenomics, one to reduce the rate of ADRs (adverse drug reactions) and to gene screen individuals to find out which dosage or drug is going to work for them best, this can then lead to personalised medicine.

A team of Swedish scientist headed by Magnus Ingelman-Sundberg in 2004, did research into a gene 

called CYP2D6. CYP2D6 is located on chromosome 22 (22q13.1)

This is chromosome 22, the yellow arrow represents the location of CYP2D6

CYP2D6 is a gene which encodes for a very important enzyme a (protein) found in the liver (Ingleman-sundberg 2004).


The structure of the Enzyme produced by CYP2D6
Boris, MT 2006, CYP2D6 Structure. Retrieved 18 March, 2012 from http://en.wikipedia.org/wiki/File:CYP2D6_structure.png


This enzyme is used to metabolise a variety of active ingredients in drugs such as Codeine, debrisoquine, antipsychotics, antidepressants, and dextromethorphan (a key active ingredient in cough medicine) (Ingleman-sundberg 2004). In 2010 Imtiaz Shah and a team of scientists investigated a drug to treat breast cancer sufferers called Tamoxifen, this drug is metabolised by CYP2D6. How ever unlike previous trials the team used pharmacogenomics to ascertain what type of metabolism levels their patient’s CYP2D6 gene produced and figured out if Tamoxifen would be suitable or not. For example in clinical trials of Oriental patients, approximately 50% had double amino acid substitution. This genotype has been shown to have higher breast cancer recurrence rate. Studies involving Caucasian cancer patients showed that patients with poor metabolisers treated with Tamoxifen 20 to 25% had cancer recurrence and higher mortality due to defective splicing or non-functional allele (Breslin 2010).
















Table 1 Common Allelic Variants of CYP2D6
CYP2D6 Variants
Mutation
Enzyme Activity
CYP2D6*2xn
Gene Duplication/amplification
Increased activity (UM)
10-30% allelic frequency in Ethiopian/Middle Eastern populations
CYP2D6*3
Frameshift deletion Non-functional allele
Inactive enzyme (PM)
1-3% frequency in Caucasian populations
CYP2D6*4
Defective splicing Non-functional allele
Inactive enzyme (PM)
20-25% allelic frequency in Caucasian populations
CYP2D6*5
Gene deletion Non-functional allele
No enzyme just under 5% allelic frequency in general populations
CYP2D6*10
Double amino acid substitution
Reduced activity due to unstable enzyme
50% allelic frequency in Oriental population
CYP2D6*17
Triple amino acid substitution
Reduced activity due to altered substrate affinity
30% frequency in African population
(Breslin et al 2010)

This leads to two issues, one people without or very little CYP2D6.  Secondly, people with gene duplications of CYP2D6 (Inglemund-sundberg 2004). People with no or very little CYP2D6 enzyme suffer problems such as some drugs show no or very little response, an increased risk of ADRs, drug metabolism too slow which can lead to high levels of toxicity in the body. This can cause severe problems in organs such as liver and kidney failure and drug dosages that are too high even if the dosage is a standard amount (Barlow-Stewart & Saleh 2007).

In contrast, people with CYP2D6 gene duplications, they can suffer from no drug response even at standard dosages or they have a too high level of metabolism which may lead to no response to a drug which means they would require higher dosages to achieve the same effect (Ingleman-sundberg 2004)
So by looking at this gene CYP2D6 and what it encodes, Magnus and Imtiaz have looked at the new possible ways to measure drugs accordingly based a person’s individual genome.  This will lead to personalised medicine and pharmacy, which will minimise the risk of ADRs, Superior clinical testing in drug design and development and reduce the number of over or under dosages in the future (Ingleman-sundberg 2004).


References

Barlow-Stewart, K and Saleh, M 2007 ‘Pharmacogenetics/Pharmacogenomics’, Produced by the centre for Genetics Education. Fact Sheet 25, retrieved 17 March, 2012 from

Boris, MT 2006, CYP2D6 Structure. Retrieved 18 March, 2012 from http://en.wikipedia.org/wiki/File:CYP2D6_structure.png

Breslin JC, Mackay PS, Shah IM & Wittayanarakul K 2010, ‘Pharmacogenetics of Cytochrome P450 2D6: A Transitional Medicine Perspective’, The Open Conference Journal, vol.1, pp. 103-108. Retrieved 18 March, 2012 from www.benthamscience.com/open/toprocj/articles/.../103TOPROCJ.pdf

Ingleman-Sundberg, M 2004, ‘Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): Clinical consequences evolutionary aspects and functional diversity’, The Pharmacogenomics Journal, Vol. 5, no.1 Viewed 15 March, 2012 http://www.nature.com/tpj/journal/v5/n1/full/6500285a.html

n.a 2012, Where is PLA2G6 Located?. Retrieved 18 March, 2012 from http://ghr.nlm.nih.gov/gene/PLA2G6

1 comment:

  1. Your article is too good and very informative, as well. Through your article, I come to know the actual difference or meaning of Pharmacy and Medicine.

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