**3.4 Muscle relaxant succinylcholine and antitubercular drug, INH**

These two conventional illustrations of pharmacogenetics involve the genetic variation along with enzymatic metabolism (enzymatic hydrolysis and acetylation). Both act as a monogenic trait and involved PK variations because of inheritance differences [71, 72]. It was observed that some patients with succinylcholine treatment experienced a serious and lethal adverse event i.e. prolonged muscle paralysis which is due to inherited "atypical" butyryl cholinesterase enzyme (BCHE). Later, it was established that BCHE allele which encodes the most usual atypical form of enzyme comprised with a nonsynonymous coding i.e. single nucleotide polymorphism (nSNP), G209 > A, results in Asp70 > Gly change in encoded amino acid which altered active sites of enzyme [73, 74]. But atypical BCHE has less ability to catalyze the succinylcholine hydrolysis and could resist to inhibition due to dibucaine compound [37, 75].

Tuberculosis is the most problematic disease of both developing as well as under-developed nations. The conformity to patients with tuberculosis is due to common lethal adverse reactions and supposed to have important aspect providing high prevalence [76, 77]. Many investigations showed that the polymorphisms of N-acetyl transferase 2 (NAT-2), CYP2E1 as well as glutathione S transferase (GST-1) would be able to influence concentration of liver toxic isoniazid metabolites in plasma. Some polymorphic genes contribute in the INH induced hepatotoxicity by

altering the anti-oxidant enzyme expression, these gene polymorphisms include glucuronosyltransferase (UGT), basic region of leucine zipper factor family (CNC) homolo (BACH), human leukocyte antigen (HLA), nitric oxide synthase (NOS) and Maf basic leucine zipper protein (MAFK). Till date the above mentioned studies encounter with many limitations [77–79].

#### **3.5 Warfarin**

Warfarin is a medication that is commonly used as an anticoagulant which means blood thinner. It aids in treating blood clots such as pulmonary embolism and deep vein thrombosis, and to prevent heart diseases associated with clotting. It has very narrow therapeutic index [80, 81]. However, warfarin therapy may result in complicated adverse reactions including both coagulation and hemorrhage. The racemic mixture of warfarin, S-form is 3–5 times more potent in comparison to R-form of an anticoagulant, and easily gets metabolized due to genetically polymorphic CYP450 isoform i.e. CYP2C9 [82]. CYP2C9 exists in two common polymorphic form, Arg144 > Cys (CYP2C9\*2) as well as Ile358 > Leu (CYP2C9\*3) modifications in coded sequence of amino acid, with nearly 12 and 5%, respectively. These forms vary between 8 and 10% in Caucasians, with minor occurrence in subject from Southeast Asia. A report in 1999, which confirms patients with one or two common CYP2C9 variant alleles, requires a "low" warfarin dose. These subjects had a risen risk of hemorrhage during warfarin therapy. In 2004, the gene encoded targeting VKORC1 (vitamin K epoxide reductase complex 1) was cloned. In a study, it was found that patients with VKORC1 type of haplotypes requires low dose, the average warfarin maintenance dose was nearly half for subjects with haplotypes having high dose maintenance. In this study, the grouping of both VKORC1 haplotyping as well as genotyping for CYP2C9 described around 25% of dose variance in warfarin. Other studies reported similar results in 2005. The Pharmacogenetics Knowledge Base (PharmGKB), in which data base is reinforced by the National Institutes of Health (NIH) along with part of the NIH Pharmacogenetics Research Network (PGRN), originated an association for consolidation of warfarin pharmacogenetic data throughout the world [83, 84]. In this evaluation of variation in genetic drug target as well as drug metabolism if and only if when VKORC1 and CYP2C9 haplotypes were determined. The figure demonstrates a schematic illustration of both pharmacokinetic (CYP2C9-dependent) as well as pharmacodynamic (VKORC1 dependent) pharmacogenomic aspects that effects final dose of warfarin (**Figure 2**).

It is important to know that by identifying the individual genetic properties, we can improve the dosing of warfarin. In general, VKORC1 haplotypes have three-fold greater effect on an individual's warfarin dose than CYP2C9. Both can play a vital role in the potential for estimating the therapeutic warfarin dose. In August 2007, FDA approved a change in labeling of warfarin package stating, "lower starting doses should be considered for patients with some genetic alterations in VKORC1 and CYP2C9 enzymes" [80].

### **4. Outlook**

These cases prove that patient care could be improved effectively by pharmacogenetic based approaches. Although, the allelic occurrences of the gene alterations must be visibly defined in the subjects studied must be well established. Out of above-mentioned cases, no one is absolute, so it is better to perform the sensitivity analyses as well as to regulate the robustness of conclusion with variation in probabilities [85, 86]. Move onward, it is utmost important for maintaining the possible

**23**

*Pharmacogenomics: Overview, Applications, and Recent Developments*

ing cost effective theragnostic in a sensible manner [90, 91].

cost-effectiveness of few recently published pharmacogenetic associated reports, for instance, vitamin K epoxide reductase gene variants envisage the warfarin response [87–89]. Lastly, it will be significant to collect pharmacoeconomic and pharmacogenetic statistics together during industry-funded clinical trials for bring-

Individualized therapeutics or tailor-made therapy is one of the major goals of pharmacogenomics. In relation to inheritance other factors also contribute to individual therapeutics due to variation in response to administration of drug. Recently many developments in the field of pharmacology and genomics have made possible for physicians to achieve individualization of therapeutics. These recent developments create possibility of thorough basis of particular drug for particular patient with motive of tailor-made therapy. Futuristic development in field of pharmacogenomics has paved the way to new emerging fields of pharmacoproteomic, pharmacotranscriptomics, and pharmacometabolomic. These new branches of science make it possible to achieve the concept of treat each patient as unique, complex, fascinating individual. At the end doubts about achieving individualized therapeutics with the help of this integrated system is still a dream

The NIPER-R communication number for this manuscript is NIPER-R/

The authors declare no conflict of interest among themselves.

*DOI: http://dx.doi.org/10.5772/intechopen.93737*

**5. Conclusion**

**Figure 2.**

*Warfarin pharmacogenomics.*

in 21st century era.

**Acknowledgements**

Communication/156.

**Conflict of interest**

*Pharmacogenomics: Overview, Applications, and Recent Developments DOI: http://dx.doi.org/10.5772/intechopen.93737*

*Drug Design - Novel Advances in the Omics Field and Applications*

encounter with many limitations [77–79].

**3.5 Warfarin**

altering the anti-oxidant enzyme expression, these gene polymorphisms include glucuronosyltransferase (UGT), basic region of leucine zipper factor family (CNC) homolo (BACH), human leukocyte antigen (HLA), nitric oxide synthase (NOS) and Maf basic leucine zipper protein (MAFK). Till date the above mentioned studies

Warfarin is a medication that is commonly used as an anticoagulant which means blood thinner. It aids in treating blood clots such as pulmonary embolism and deep vein thrombosis, and to prevent heart diseases associated with clotting. It has very narrow therapeutic index [80, 81]. However, warfarin therapy may result in complicated adverse reactions including both coagulation and hemorrhage. The racemic mixture of warfarin, S-form is 3–5 times more potent in comparison to R-form of an anticoagulant, and easily gets metabolized due to genetically polymorphic CYP450 isoform i.e. CYP2C9 [82]. CYP2C9 exists in two common polymorphic form, Arg144 > Cys (CYP2C9\*2) as well as Ile358 > Leu (CYP2C9\*3) modifications in coded sequence of amino acid, with nearly 12 and 5%, respectively. These forms vary between 8 and 10% in Caucasians, with minor occurrence in subject from Southeast Asia. A report in 1999, which confirms patients with one or two common CYP2C9 variant alleles, requires a "low" warfarin dose. These subjects had a risen risk of hemorrhage during warfarin therapy. In 2004, the gene encoded targeting VKORC1 (vitamin K epoxide reductase complex 1) was cloned. In a study, it was found that patients with VKORC1 type of haplotypes requires low dose, the average warfarin maintenance dose was nearly half for subjects with haplotypes having high dose maintenance. In this study, the grouping of both VKORC1 haplotyping as well as genotyping for CYP2C9 described around 25% of dose variance in warfarin. Other studies reported similar results in 2005. The Pharmacogenetics Knowledge Base (PharmGKB), in which data base is reinforced by the National Institutes of Health (NIH) along with part of the NIH Pharmacogenetics Research Network (PGRN), originated an association for consolidation of warfarin pharmacogenetic data throughout the world [83, 84]. In this evaluation of variation in genetic drug target as well as drug metabolism if and only if when VKORC1 and CYP2C9 haplotypes were determined. The figure demonstrates a schematic illustration of both pharmacokinetic (CYP2C9-dependent) as well as pharmacodynamic (VKORC1 dependent) pharmacogenomic aspects that effects final dose of warfarin (**Figure 2**). It is important to know that by identifying the individual genetic properties, we can improve the dosing of warfarin. In general, VKORC1 haplotypes have three-fold greater effect on an individual's warfarin dose than CYP2C9. Both can play a vital role in the potential for estimating the therapeutic warfarin dose. In August 2007, FDA approved a change in labeling of warfarin package stating, "lower starting doses should be considered for patients with some genetic alterations in VKORC1

These cases prove that patient care could be improved effectively by pharmacogenetic based approaches. Although, the allelic occurrences of the gene alterations must be visibly defined in the subjects studied must be well established. Out of above-mentioned cases, no one is absolute, so it is better to perform the sensitivity analyses as well as to regulate the robustness of conclusion with variation in probabilities [85, 86]. Move onward, it is utmost important for maintaining the possible

**22**

and CYP2C9 enzymes" [80].

**4. Outlook**

cost-effectiveness of few recently published pharmacogenetic associated reports, for instance, vitamin K epoxide reductase gene variants envisage the warfarin response [87–89]. Lastly, it will be significant to collect pharmacoeconomic and pharmacogenetic statistics together during industry-funded clinical trials for bringing cost effective theragnostic in a sensible manner [90, 91].
