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50904989 MT5004
Introduction
Therapeutics would have been a lot easier if the response to the dose of
drugs were always the same. But in practice, there exists an inter-individual
variability in the response exhibited for same dose of a drug (Fromm, 1997).
Inter-individual variable response is a major issue affecting
pharmacotherapy. Inter-individual variable drug response can be attributed
to genetic polymorphism in drug metabolizing enzymes or in drug
transporters. (Marin, 2009). This variability may explain the efficacy of a
drug in a given patient as well as its adverse side effects. (Marin, F.2009).
The most commonly occurring genetic variation that affects drug action is
single nucleotide polymorphism (SNP) (Pfost, 2000) (refer fig 1).
Fig 1. Showing Single Nucleotide polymorphism
In 1980’s, Frank Gonzalez discovered that the basis for poor debrisoquine
metabolism, which affected 8% of Caucasian population, was defective
cytochrome P450 2D6 enzyme. Later many molecular defects have been
linked to variations in cytochrome P450 which is a drug metabolizing
enzyme. (Maxwell, 2006)
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Student ID No. 50904989 MT5004
Pharmacogenetics involves the use of DNA analysis techniques to list out the
variations within the human genome specially SNPs –so that the new or
existing therapeutic agents can be used with maximal efficacy and minimal
toxicity. (Pfost, 2000).Pharmacogenetics is of utmost importance for drugs
which have a narrow therapeutic range between effectiveness and toxicity.
(AMEYAW, 2006)
Pharmacogenetics as a process
There are three major phases in pharmacogenetics process:
(1) Discovering SNP: It involves identification and listing of SNPs in the
human genome and out of these SNP’s some affect drug response or cause
toxicity.
(2) Clinical trails are designed and conducted to perform genetic analysis so
that clinical association between SNP and variation in drug response could be
established.
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Chemicals and drugs can influence the activity of CYP2B6 either by inducing
it or inactivating it (Flockhart, 2009).
The studies conducted by researchers showed that over 100 SNP’s exists in
the (Lang, et al.,2004) CYP2B6 and there exists 28 alleles but other studies
showed that there exists several more DNA variations in the entire CYP2B6.
Polymorphism of CYP2B6 causes partial diminished activity, non-function or
increase in function of CYP2B6 genes (Flockhart, 2009).
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Cytochrome P450 2C are of 4 types (2C8, 2C9, 2C18 and 2C19) and are
expressed in liver. Among these isoforms 2C9 and 2C19 are shown to exhibit
extensive polymorphism (Ishizaki, 2002).CYP2C9 is located on long arm of
chromosome 10, which also contains genes for CYP2C8, 2C18 and 2C19
(Flockhart,2009).
CYP2C9 is the most abundant of all the CYP enzyme found in liver and shows
a selectivity for the oxidation of small, lipophilic anions such as ibuprofen,
diclofenac and gemfiborzil as substrates (Zhou, 2009).
CYP 2C9 and 2C19 metabolize important therapeutic drugs e.g. metabolism
of the anticoagulant warfarin by Cytochrome P4502C9. Warfarin is an
inhibitor of vitamin K dependent clotting factors. (Maxwell, 2006)
A study conducted has found, 556 SNPs in the CYP2C9 upstream sequence
which influences the activity of CYP2C9. (Refer table 1) CYP2C9*2 and
CYP2C9*3 are the variants which have 12% and 5% activity that of the wild
type allele. Therefore, require much lower doses of warfarin, than the
patients with the wild type gene. (Maxwell, 2006)
Table 1. Polymorphic CYP2C isoforms and its substrates, inhibitors and inducers.
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Table 2. CYP2C9 allelic variants and their frequencies in various ethnic populations.
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CYP2C9 allelic variants and the frequencies have been listed from various
ethnic populations (refer Table 2). Polymorphisms in the exon 3, exon 7and
exon 8 of gene CYP2C9 was determined for different ethnicities of world.
(refer table 2.) (Ishizaki, 2002).
Patients who were homozygous for the genotype CYP2C9*3 and those who
were heterozygous CYP2C9*1/*3 genotype had drastically reduced clearance
of (S)-warfarin. The reduction in clearance was 60%- 90% (refer graph 1.)
(Takahashi, 2001), indicating the need for adjusted dosage of warfarin for
CYP2C9 genotype. Polymorphism of CYP2C9 also influences the risk of
bleeding (Ishizaki, 2002).
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aromatic ring. CYP2C9 is the main enzyme responsible for the hydroxylation.
Since CYP2C9 is the principle enzyme in the metabolism of sulfonylureas,
mutant allele CYP2C9*3 has been clearly linked to impaired clearance of
sulfonylureas (Kirchheiner, J., et al.,2002).
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times high risk of bleeding complications, than a normal patient (Gage et al.,
2008).
Cytochrome P4502C19
In humans, metabolism of clinically available mephenytoin is stereospecific.
(Kupfer,1984) Out of the two enantiomers of Mephenytoin, R enantiomer is
metabolized by CYP3A4 and is demethylated to nirvanol while S enantiomer
is hydroxylated by CYP2C19 (Kupfer,1984). Polymorphism in CYP2C19 which
metabolizes S enantiomers results in two phenotypes – Extensive
metabolizers (EM) and Poor metabolizers (PM) (Kupfer,1984).
Proton pump inhibitors are metabolized by CYP2C19 and a few PPI’s are
omeprazole, lansoprazole, pantoprazole, and rabeprazole. (Andersson,1996).
Rabeprazole showed a very small difference in its AUC values for Poor
metabolizers and for Extensive metabolizers as compared to the other 3
PPI’s. Indicating no significant effect of CYP2C19 polymorphism on
disposition of Rabeprazole (Andersson,1996). The most affected by CYP2C19
polymorphism was omeprazole in which PMs showed 20 times more AUC
value than EMs followed by pantoprazole and iansoprazole and least affected
was rabeprazole. PPIs on repeated doses showed increased acid suppression
which is positive relationship between polymorphism and pharmacological
effect (Ishizaki, 2002).
From the above facts, we can suggest that doing genotyping for CYP2C19 is
important in terms of efficacy and toxicity of drugs for patients suffering
from acid-related disease treatments.
Conclusion
Overall impact of pharmacogenetics will be to improve patient-care
processes, and public health. This can be achieved both by optimization of
drug prescribing and by improvements in new drug development. With the
knowledge of pharmacogenetics doctors will be able to avoid prescribing
drugs to those patients who are unlikely to respond or who are more prone
to adverse reactions.
Preventing toxicity and improving efficacy of the drugs will not only help
patients but will also help save millions of pounds of health-care budget.(
AMEYAW,2006)
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References:
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– Lal, S., Jada, S.R., Xiang, X., Lim,W.T., Lee, E.J., Chowbay, B.,(2006).
Pharmacogenetics of target genes across the warfarin pharmacological
pathway. Clin. Pharmacokinet. Vol 45,p 1189–1200.
– Marin, F.,et al. (2009).Pharmacogenetics in Cardiovascular
Antithrombotic Therapy. Journal of the American College of Cardiology.
Vol. 54, No. 12.
– Maxwell,J.R., Wilson,A.G. (2006).Cytokine pharmacogenetics.
Cytokine .Vol 33. p 362-366
– Pfost, D.R., Boyce-Jacino,M.T., Grant,D.M,(2000).A SNPshot:
pharmacogenetics and the future of drug therapy. TIBTECH. (Vol. 18)
– Robert, J., et al.(2005). Predicting drug response and toxicity based on
gene polymorphisms. Critical Reviews in Oncology/Hematology. Vol 54.
p 171–196
– Suzuki, K., et al. (2006). Effect of CYP2C9 genetic polymorphisms on
the efficacy and pharmacokinetics of glimepiride in subjects with type
2 diabetes. Diabetes Research and Clinical Practice. Vol 72. p148–154.
– Takahashi, H., Echizen, H. (2001).Pharmacogenetics of
warfarin elimination and its clinical implications, Clin.
Pharmacokinet. Vol 40.p 587– 603.
– Takahashi, H., Echizen, H., (2001). Pharmacogenetics of warfarin
elimination and Its clinical implications. Clin. Pharmacokinet. Vol 40, p
587–603.
– Zhou, S.F., Zhou, W.Z., Huang, M. (2009).Polymorphisms of human
cytochrome P450 2C9 and the functional relevance. Online first
– Flockhart,D.A., Desta,Z. (2009) Pharmacogenetics of Drug Metabolism.
Clinical and Translational Science.p 301-317.
– Lang , T. , et al. (2004) Multiple novel nonsynonymous CYP2B6 gene
polymorphisms in Caucasians: demonstration of phenotypic null alleles
. J. Pharmacol. Exp. Ther. 311 ( 1 ) ,p 34 – 43 .
– Zanger , U.M., et al. ( 2007 ) Polymorphic CYP2B6: molecular
mechanisms and emerging clinical significance . Pharmacogenomics 8
( 7 ) , 743- 759 .
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