Clincial pharmacogenetics and potential application in personalized medicine

Zhou, Shu-Feng, Di, Yuan Ming, Chan, Eli, Du, Yao-Min, Chow, Vivian, Xue, Charlie C., Lai, Xinsheng, Wang, Jian-Cheng, Li, Chun Guang, Tian, Min and Duan, Wei 2008, Clincial pharmacogenetics and potential application in personalized medicine, Current drug metabolism, vol. 9, no. 8, pp. 738-784.

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Title Clincial pharmacogenetics and potential application in personalized medicine
Author(s) Zhou, Shu-Feng
Di, Yuan Ming
Chan, Eli
Du, Yao-Min
Chow, Vivian
Xue, Charlie C.
Lai, Xinsheng
Wang, Jian-Cheng
Li, Chun Guang
Tian, Min
Duan, Wei
Journal name Current drug metabolism
Volume number 9
Issue number 8
Start page 738
End page 784
Total pages 47
Publisher Bentham Science Publishers Ltd.
Place of publication Hilversum, Netherlands
Publication date 2008-10
ISSN 1389-2002
1875-5453
Keyword(s) pharmacogenetics;
drug metabolizing enzymes
cytochrome P450
CYP3C9
CYP2D6
P-glycoprotein
single nucleotide polymorphism
thiopurine S-methyltransferase
β-adrenergic receptor
Summary The current `fixed-dosage strategy' approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current  pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in  personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these  individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport  polymorphism, the most extensively studied drug transporter is  P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drug's distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the β2-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.
Language eng
Field of Research 111502 Clinical Pharmacology and Therapeutics
Socio Economic Objective 929999 Health not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
HERDC collection year 2008
Persistent URL http://hdl.handle.net/10536/DRO/DU:30017726

Document type: Journal Article
Collection: School of Medicine
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