**8. Conclusion**

healthy subjects and those with cardiovascular disease, the odds ratio was 1.14 (P=0.40). The PLA2 allele occurs with a frequency of approximately 15% in humans and has been associat‐

Associations between the PLA polymorphisms and subacute thrombosis after coronary in‐ tervention have been described in some reports [139-141] and it was shown that an in‐ creased risk of subacute thrombosis is associated with the PLA2 allele. In one study, the risk of subacute thrombosis after coronary angioplasty and stent placement was five times great‐ er in coronary artery disease patients with the PLA2 polymorphism than in patients homo‐ zygous for the PLA1 allele, despite similar antiplatelet therapy and similar clinical,

The obvious candidates for pharmacogenetic analysis are genes involved in clopidogrel me‐ tabolism. Clopidogrel is a prodrug and its active form, thiol, is formed during the biotrans‐ formation in the liver. CYP2C19, CYP3A4/5, CYP1A2, and CYP2B6 are involved in this

P2Y12 belongs to the G protein-coupled purinergic receptor for adenosine diphosphate (ADP). The P2Y12 protein is found mainly, but not exclusively, on the surface of blood pla‐ telets, and is an important regulator in blood clotting. The active clopidogrel metabolite irre‐ versibly binds to platelet ADP P2Y12 receptors. ADP P2Y12 receptors and loss-of-function CYP2C19\*2 was identified as the single major genetic determinant of biochemical response to clopidogrel, accounting for approximately 12% of the variation in ADP-stimulated plate‐ let aggregation during drug treatment [143]. CYP2C19\*2 carriers treated with clopidogrel have an increased risk for major adverse cardiovascular events compared to noncarriers and

Loss-of-function CYP2C19\*2 allele has been reproducibly shown to be associated with a de‐ creased conversion of clopidogrel into its active metabolite, reduced antiplatelet effect and

The frequency of CYP2C19\*2 polymorphism varies in different populations: in Caucasian, African American, and Mexicans it presence is 18% to 33% (2%–3% homozygotes) and the allele frequency is higher in Asians. The loss-of-function \*3 variant is also associated with

P-glycoprotein, also known as multidrug resistance protein 1 (MDR1) or ATP-binding cas‐ sette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243), is a glyco‐ protein that in humans is encoded by the ABCB1 gene. ABC transporters are transmembrane proteins that utilize the energy of adenosine triphosphate hydrolysis to car‐ ry out certain biological processes including translocation of various substrates across mem‐ branes and non-transport-related processes such as translation of RNA and DNA repair. Contradicting results have been reported for variants in ABCB1 and Gln192Arg allele in par‐ aoxonase 1, which have been implicated in clopidogrel responsiveness. These associations

increased risk for cardiovascular events in patients using clopidogrel [4, 145].

poorer response and is highly prevalent in Asians [146, 147].

ed with increased platelet activation and aggregation in vitro [138].

angiographic and procedural characteristics [139].

increased risks of stent thrombosis [144].

need further confirmation [148-150].

**7.2. Clopidogrel**

88 Drug Discovery

process [142].

Adverse drug reactions (ADRs) have been reported to be the cause for drug withdrawal af‐ ter marketing, hospital admissions, death in hospitalised patients and to be the fourth lead‐ ing cause of death in developed countries. The costs associated with ADRs may radically escalate the cost for healthcare.

There is an increasing use of multiple medications to treat patients with chronic illnesses. Drug-drug interactions are common and growing in frequency due to increasing numbers of medications available and the number of patients on multiple medications. The knowledge of the pharmacodynamics and pharmacokinetics of the drugs helps to avoid unintended and problematic drug interactions. Several web sites, books, and cards are available for the clinician. The web sites are updated on a regular basis and are useful tools for prescribers.

The necessity to understand drug combination pharmacokinetics and pharmacodinamics in drug interactions is illustrated by the following example: a patient who is taking a drug equally cleared by CYP2D6 and CYP3A. That patient may not be at substantial risk for toxicity when treated with either a CYP2D6 or CYP3A inhibitor alone, but may be if treat‐ ed with both inhibitors at the same time [151]. Pharmacodynamic or pharmacokinetic drug interaction is a complex process and includes understanding of individual variations in drug metabolism.

Pharmacogenetics has a potential role in reducing ADRs at the pre-marketing and post-mar‐ keting stages of drug development and in clinical care. A priori identification of individuals at risk of developing ADRs for a given drug will help develop strategies to reduce the risk for ADRs in these patients. It can also be used to identify individuals at risk of developing serious ADRs and to treat these individuals with alternative therapy, thus converting ADRs that are traditionally considered unavoidable to avoidable ADRs.

Although pharmacogenetics is a highly complex and ever-evolving science, it has amassed knowledge that can readily be used to provide efficient care to patients. It has been shown that gene variants that play a role in drug metabolism pathways can alter a patient's re‐ sponse or increase toxicity at normal dosage range, especially in combinational drug treat‐ ments. Pharmacogenetics seeks to understand the nature of variable drug responses. Several pharmacogenetics tests are already available for cardiovascular medications in biomedical laboratories (Table 1).

Pharmacogenetic findings may help to explain ethnic differences in drug response. The ac‐ cumulated facts of ethnic differences in cardiovascular drug responses and the fact that many genetic polymorphisms differ in frequency on the basis of ethnicity (example in the Western Sydney population, Fig. 1) will undoubtedly support future development of phar‐ macogenetics in patient care and in drug interaction interpretation.

It is possible that use of genetic and other patient-specific information, including envi‐ ronmental factors will help guide drug therapy decisions for certain drugs and drug combinations.

**Appendix**

**Glossary of some Pharmacogenetic Terms**

iants of modest effect.

unit.

multiple genes.

chromosomes in an individual.

www.pharmgkb.org/#public

**Useful Internet Resources and databases:**

www.ncbi.nlm.nih.gov/sites/entrez?db=snp

**• Allele:** An alternative form of a gene at a given locus.

**• Genetic polymorphism:** Minor allele frequency of ≥1% in the population.

included in every cell of the human body, apart from the red blood cells.

an individual, i.e. the specific allelic makeup of an individual.

**• Phenotype:** Observable expression of a particular gene or genes.

mation (NCBI): www.ncbi.nlm.nih.gov/sites/entrez?db=omim

**• Heterozygote:** A person who has two copies of an allele that are different.

**• Homozygote:** A person who has two copies of an allele that are the same.

**• Genome:** The complete DNA sequence of an organism. Sum total of the genetic material

Drug Interactions, Pharmacogenomics and Cardiovascular Complication

http://dx.doi.org/10.5772/48423

91

**• Genomewide association study (GWAS):** A genetic association study in which the densi‐ ty of genetic markers and the extent of linkage disequilibrium are sufficient to capture a large proportion of the common variation in the human genome in the population under study, and the number of specimens genotyped provides sufficient power to detect var‐

**• Genotype:** The alleles at a specific locus an individual carries. The genetic constitution of

**• Haplotype:** A group of alleles from two or more loci on a chromosome; inherited as a

**• Pharmacogenetics:** A study of genetic causes of individual variations in drug response. In this review, the term "pharmacogenetics" is interchangeable with "pharmacogenomics."

**• Pharmacogenomics:** Genomewide analysis of the genetic determinants of drug efficacy and toxicity. Pharmacogenetics focuses on a single gene while pharmacogenomics studies

**• Single nucleotide polymorphism (SNP):** is a DNA sequence variation occurring when a single nucleotide in the genome differs between members of a biological species or paired

**•** OMIM (Online Mendelian Inheritance in Man), National Centre for Biotechnology Infor‐

**•** PharmGKB (The Pharmacogenetics and Pharmacogenomics Knowledge Base):

**•** NCBI, Individual SNP information, such as genetic location, nucleotide and amino acid changes, and allele frequencies in diverse populations, can be obtained from dbSNP:

**Figure 1.** Example of diversity in prevalence of clinically relevant polymorphisms. (\*Western Sydney Population com‐ bined data. WSLHD population is a mix of Caucasians, Asians and Africans.)
