**6. The effect of CYP2C19 genotypes on the pharmacokinetics**

Previous studies in patients with different CYP2C19 genotypes reported not to affect plasma *R*-warfarin concentrations at the steady state in clinical studies, in which the concentrations were evaluated at a one sampling point (Obayashi K et al., 2006; Scordo MG et al., 2002; Takahashi et al., 1998). However, two of the reports (Obayashi K et al., 2006; Scordo MG et al., 2002) observed that the *S*/*R* ratio based on steady-state concentrations in PMs was smaller than that in hmEMs. The third study (Takahashi et al., 1998) compared PMs with EMs which included both hmEMs and heterozygous EMs with one mutated CYP2C19 allele. Therefore, the present study was designed to evaluate the elimination phase of warfarin and examine the effect of the CYP2C19 genotype on the pharmacokinetics of warfarin enantiomers. Although the pharmacokinetics was measured after a single administration in this study, our results indicated that the plasma concentrations and t1/2 of *R*-warfarin in PMs were markedly higher compared with those of the corresponding *R*-enantiomer in hmEMs. In addition, the AUC0-<sup>∞</sup> *S*/*R* ratio in PMs decreased significantly more than that in hmEMs, thereby showing that the

Warfarin Enantiomers Pharmacokinetics by CYP2C19 229

concentrations. Therefore, these studies suggest that VKORC1 activity may be an important

These results indicate that CYP2C19 activity is important in the pharmacokinetics of *R*warfarin because the pharmacokinetics of warfarin enantiomers were different between the CYP2C19 genotypes and the omeprazole affected the *R*-warfarin pharmacokinetics of CYP2C19 in only hmEMs. However, these affects are not translated into any significant

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Kubota T, Chiba K, Ishizaki T. (1996). Genotyping of S-mephenytoin 4'-hydroxylation in an extended Japanese population. *Clin Pharmacol Ther*, Vol. 60, pp. 661-666. Lilja JJ, Backman JT, Neuvonen PJ. (2005). Effect of gemfibrozil on the pharmacokinetics and

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the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. *Drug Metab* 

gene variations are the major contributors of variation in warfarin dose in Japanese

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**8. Conclusion** 

**9. References** 

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*Dispos*, Vol. 32, pp. 821-7.

effect in the pharmacodynamics of warfarin.

pharmacokinetics of *R*-warfarin may be significantly affected by CYP2C19 polymorphism. In contrast, no difference was found in any pharmacokinetic parameters of *S*-warfarin between the hmEMs and the PMs. Consequently, these findings suggest that CYP2C19 activity is an important determinant of *R*-warfarin pharmacokinetics.

We also demonstrated that the reported interaction of *R*-warfarin with omeprazole was found only in the hmEMs of CYP2C19. In previous pharmacokinetic studies (Sutfin T et al., 1989; Unge P et al., 1992), omeprazole has been reported to cause a minor but significant increase in *R*-warfarin plasma concentrations [9.5% (Unge P et al., 1992) and 12% (Sutfin T et al., 1989)]. In our present study, although the pharmacokinetics of warfarin enantiomers of the PMs were not affected by the omeprazole treatment, mean *R*-warfarin AUC0-∞ and t1/2 of the hmEMs increased after the omeprazole treatment to the levels comparable to those of the PMs. Mean *R*-warfarin AUC0-∞ of our hmEMs showed an 18 % increase, and the increase was greater than that of the previous studies (Sutfin T et al., 1989; Unge P et al., 1992), probably due to recruiting the same genotype in the present study. Omeprazole is known to be an inhibitor of some CYP enzymes including CYP2C9 and 2C19 (Ko JW et al., 1997; Li XQ et al., 2004). CYP2C9 is known to be responsible for the biotransformation from *S*-warfarin to *S*-7-hydroxywarfarin **(**Kaminsky LS and Zhang ZY, 1997**)**, and the ratio of *S*-7 hydroxywarfarin AUC to *S*-warfarin AUC would reflect the *in vivo* activity of CYP2C9. Previous report suggested that the clearance of omeprazole is markedly reduced and plasma concentrations of omeprazole in CYP2C19 PMs are much more elevated than those in CYP2C19 EMs (Sohn DR et al., 1992). Increased plasma concentrations of omeprazole in CYP2C19 PMs might affect the pharmacokinetics of warfarin *S*-enantiomer, a substrate of CYP2C9 **(**Kaminsky LS and Zhang ZY, 1997**)**, as well as its *R*-enantiomer, compared to those in CYP2C19 EMs. In this study, the inhibitory effect of omeprazole was noted only in the hmEMs of CYP2C19 despite higher omeprazole concentrations in the PMs, and the AUC0-<sup>∞</sup> ratio of *S*-7-hydroxywarfarin to *S*-warfarin was relatively constant between the placebo and the omeprazole phases, suggesting that the 7-day administration of omeprazole 20 mg once daily would affect the CYP2C19 activity solely.

#### **7. The effect of CYP2C19 genotypes on the pharmacodynamics**

Interestingly, no significant difference was found in PT-INR between the hmEMs and PMs in both the control and the omeprazole phases even though the CYP2C19 genotypes affected the *R*-warfarin pharmacokinetic parameters. However, these findings are not surprising because the anticoagulant effect of *S*-enantiomer is 3-5 times more potent than that of *R*enantiomer (Takahashi H and Echizen H, 2001), and a concentration rises of *R*-enantiomer was seemed to have little influence on the anticoagulant effect of warfarin. These results therefore suggest that altered pharmacokinetics of *R*-warfarin may play a minor role in determining the average clinical doses of warfarin. Moreover, these results also imply that inhibition of the *in vivo* CYP2C19 activity by the co-administration of a CYP2C19 inhibitor, such as omeprazole, lansoprazole or fluvoxamine (Hemeryck A and Belpaire FM, 2002; Ko JW et al., 1997; Li XQ et al., 2004), may scarcely modify the anticoagulant effects of warfarin. Recently, Rieder et al. (2005) have shown that there is an effect of the VKORC1 on dose requirement. Furthermore, Obayashi et al. (2006) reported that the genotyping of the vitamin K epooxide reductase complex subunit 1 gene (VKORC1) may be more predictive of the anticoagulant effect than genotyping of CYPs, which reflects the warfarin plasma concentrations. Therefore, these studies suggest that VKORC1 activity may be an important determinant of the pharmacodynamics of warfarin in Japanese patients.

#### **8. Conclusion**

228 Pharmacology

pharmacokinetics of *R*-warfarin may be significantly affected by CYP2C19 polymorphism. In contrast, no difference was found in any pharmacokinetic parameters of *S*-warfarin between the hmEMs and the PMs. Consequently, these findings suggest that CYP2C19

We also demonstrated that the reported interaction of *R*-warfarin with omeprazole was found only in the hmEMs of CYP2C19. In previous pharmacokinetic studies (Sutfin T et al., 1989; Unge P et al., 1992), omeprazole has been reported to cause a minor but significant increase in *R*-warfarin plasma concentrations [9.5% (Unge P et al., 1992) and 12% (Sutfin T et al., 1989)]. In our present study, although the pharmacokinetics of warfarin enantiomers of the PMs were not affected by the omeprazole treatment, mean *R*-warfarin AUC0-∞ and t1/2 of the hmEMs increased after the omeprazole treatment to the levels comparable to those of the PMs. Mean *R*-warfarin AUC0-∞ of our hmEMs showed an 18 % increase, and the increase was greater than that of the previous studies (Sutfin T et al., 1989; Unge P et al., 1992), probably due to recruiting the same genotype in the present study. Omeprazole is known to be an inhibitor of some CYP enzymes including CYP2C9 and 2C19 (Ko JW et al., 1997; Li XQ et al., 2004). CYP2C9 is known to be responsible for the biotransformation from *S*-warfarin to *S*-7-hydroxywarfarin **(**Kaminsky LS and Zhang ZY, 1997**)**, and the ratio of *S*-7 hydroxywarfarin AUC to *S*-warfarin AUC would reflect the *in vivo* activity of CYP2C9. Previous report suggested that the clearance of omeprazole is markedly reduced and plasma concentrations of omeprazole in CYP2C19 PMs are much more elevated than those in CYP2C19 EMs (Sohn DR et al., 1992). Increased plasma concentrations of omeprazole in CYP2C19 PMs might affect the pharmacokinetics of warfarin *S*-enantiomer, a substrate of CYP2C9 **(**Kaminsky LS and Zhang ZY, 1997**)**, as well as its *R*-enantiomer, compared to those in CYP2C19 EMs. In this study, the inhibitory effect of omeprazole was noted only in the hmEMs of CYP2C19 despite higher omeprazole concentrations in the PMs, and the AUC0-<sup>∞</sup> ratio of *S*-7-hydroxywarfarin to *S*-warfarin was relatively constant between the placebo and the omeprazole phases, suggesting that the 7-day administration of omeprazole 20 mg once

activity is an important determinant of *R*-warfarin pharmacokinetics.

daily would affect the CYP2C19 activity solely.

**7. The effect of CYP2C19 genotypes on the pharmacodynamics** 

Interestingly, no significant difference was found in PT-INR between the hmEMs and PMs in both the control and the omeprazole phases even though the CYP2C19 genotypes affected the *R*-warfarin pharmacokinetic parameters. However, these findings are not surprising because the anticoagulant effect of *S*-enantiomer is 3-5 times more potent than that of *R*enantiomer (Takahashi H and Echizen H, 2001), and a concentration rises of *R*-enantiomer was seemed to have little influence on the anticoagulant effect of warfarin. These results therefore suggest that altered pharmacokinetics of *R*-warfarin may play a minor role in determining the average clinical doses of warfarin. Moreover, these results also imply that inhibition of the *in vivo* CYP2C19 activity by the co-administration of a CYP2C19 inhibitor, such as omeprazole, lansoprazole or fluvoxamine (Hemeryck A and Belpaire FM, 2002; Ko JW et al., 1997; Li XQ et al., 2004), may scarcely modify the anticoagulant effects of warfarin. Recently, Rieder et al. (2005) have shown that there is an effect of the VKORC1 on dose requirement. Furthermore, Obayashi et al. (2006) reported that the genotyping of the vitamin K epooxide reductase complex subunit 1 gene (VKORC1) may be more predictive of the anticoagulant effect than genotyping of CYPs, which reflects the warfarin plasma These results indicate that CYP2C19 activity is important in the pharmacokinetics of *R*warfarin because the pharmacokinetics of warfarin enantiomers were different between the CYP2C19 genotypes and the omeprazole affected the *R*-warfarin pharmacokinetics of CYP2C19 in only hmEMs. However, these affects are not translated into any significant effect in the pharmacodynamics of warfarin.

#### **9. References**


**1. Introduction** 

 \*

Corresponding Author

**12** 

*India* 

**Pharmacogenetics –** 

Anjana Munshi\* and Vandana Sharma

*Osmania University, Begumpet, Hyderabad,* 

*Institute Of Genetics and Hospital for Genetic Diseases,* 

**A Treatment Strategy for Alcoholism** 

Alcoholism is a complex relapsing disorder of heterogeneous etiology, affecting people internationally. Alcohol dependence is a cumulative response of inability to stop drinking, craving and developing the symptoms of physical dependence and tolerance. In past two decades, mounting evidence has suggested that alcoholism or alcohol addiction is a host of major psychological, social, financial and health problems (Poznyak et al., 2005). According to World Health Organization, alcoholism is responsible for 4% of global disease burden and is the third major preventable risk factor for premature death and disability in developed nations (World Health Organization, 2002). Although, the exclusive biological mechanisms underlying the development of alcoholism are still uncertain, the major risk factors contributing towards the development of alcoholism are age (adolescents are at higher risk of developing alcoholism), gender (men are more prone to develop alcoholism as compared to women due to depression), personality (experience seeking), and psychiatric or behavioral disorders. The prevalence, age of onset, clinical symptoms and outcome of alcoholism differs from individual to individual and varies according to ethnicity (Kenneth et al., 2011). In addition to this, lower social status and low education have also been found to be associated with alcoholism in cross sectional and longitudinal studies (Fukuda et al.,

According to World Health Organization report on global alcohol status, it has been found that approximately 2 billion people consume alcoholic beverages and there are about 76.3 million people with diagnosable alcohol disorder (World Health Organization, 2004). In India the prevalence of alcoholism has been found to be 21.4% as recoded by epidemiological surveys (Benegal, 2005).The deleterious effects of alcohol on central nervous system can be observed in the form of changes in mood and personality, anxiety and depression. Although, it affects all the organs in the body, brain neurotransmitters are the main target sites of alcohol (Wertheimer et al., 2003). The specific physiological effects of alcohol depend on dose, concentration in blood, absorption, distribution, metabolism, excretory conditions, prior drinking experience, concurrent use of other drugs, and

2005; Poznyak et al., 2005; Subramanian et al., 2005; Wray et al., 2005).

