**3. Pharmacokinetics of warfarin enantiomers**

We examined the pharmacokinetics of warfarin enantiomers by administering 10 mg of racemic warfarin to 17 healthy volunteers (Uno T et al., 2008). Blood samples were obtained before and over the course of 120 hours after dosing for the determination plasma warfarin enantiomer concentrations and prothrombin time-INR (PT-INR). Fig. 2 shows the mean plasma concentration-time curves for *R*- and *S*-warfarin between the CYP2C19 genotypes. The mean pharmacokinetic parameters of these compounds are summarized in Table 1.

In this study, the area under the plasma concentration-time curve (AUC0-∞) and the elimination half-life (t1/2) of *R*-warfarin were about 2-fold greater than those of *S*-warfarin in 17 subjects (Table 1). These values of *R*- and *S*-warfarin were in line with a previous report in which the same dose of racemic warfarin was administered (Lilja JJ et al., 1984). Additionally, AUC0-∞ and t1/2 of *R*-warfarin in PMs were significantly greater than those in hmEMs (*P* < 0.001 and *P =* 0.010, respectively). Similarly, there is a significant difference (*P =*  0.007) in the apparent oral clearance (CL) in hmEMs compared with that in PMs. The *S*/*R* ratios of AUC0-∞ of warfarin enantiomers were 0.51 in hmEMs and 0.37 in PMs (*P =* 0.005). Whereas, no difference was found in all pharmacokinetic parameters of *S*-warfarin and *S*-7 hydroxywarfarin in hmEMs compared with PMs of CYP2C19.

Warfarin Enantiomers Pharmacokinetics by CYP2C19 227

AUC, area under plasma concentration-time curve; Cmax, peak concentration; tmax, time to Cmax; t1/2, elimination half-life; CL, apparent oral clearance. The S/R ratios of AUC; AUC0-∞ *S*-warfarin / AUC0-<sup>∞</sup>

No significant difference was found between hmEMs and PMs in either the PT-INR AUC0- 120 or the PT-INR max during the placebo phase, and the omeprazole treatment did not

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

*<sup>R</sup>*-warfarin. The metabolic ratio; AUC0-∞ of *S*-7-hydroxywarfarin / AUC0-∞ of *<sup>S</sup>*-warfarin. \* *P* <0.05,\*\**P <*0.01, \*\*\**P* <0.001*,* between hmEMs and PMs., **†***P* <0.05,**††***P* <0.01, between control and omeprazole phase. Data are shown as mean and 95% confidence interval ; tmax and fold change data are

Table 1. The summary of pharmacokinetics of warfarin enantiomers

affect these parameters in both hmEMs and PMs (Uno T et al., 2008).

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

shown as a median wich a range.

**5. Pharmacodynamics of warfarin** 

Fig. 2. Plasma concentrations-time curves (mean + S.D.) of *R*-warfarin or *S*-warfarin in hmEMs (*R*-; open circles, *S*-; open square) and PMs (*R*-; closed circles, *S*-; closed square) after a single dose of 10 mg warfarin.

#### **4. Drug interaction between omeprazole and warfarin enantiomers**

Omeprazole 20 mg/daily was given orally to 17 healthy volunteers for 11 days, and on day 7, a single dose of racemic warfarin 10 mg was added (Uno T et al., 2008).

The pharmacokinetic parameters are summarized in Table 1. In hmEMs, the omeprazole treatment significantly increased *R*-warfarin AUC0-∞ (*P* = 0.004), and prolonged its t1/2 (*P* = 0.017) without any effect on *R*-warfarin Cmax or tmax. However, the omeprazole treatment did not alter any pharmacokinetic parameters of *S*-warfarin in both hmEMs and PMs as well as those of *R*-warfarin in hmEMs. Consequently, the omeprazole treatment decreased the *S*/*R* enantiomer ratio of warfarin AUC0-∞ from 0.51 to 0.43 in hmEMs (*P* = 0.010), but not in PMs.

In addition, significant differences were found in mean Cmax (*P* < 0.001), t1/2 (*P* = 0.005), and AUC0-24 (*P* < 0.001) of omeprazole between different CYP2C19 genotypes, though there was no difference in mean Cmax or AUC0-24 of 5-hydroxyomeprazole between hmEMs and PMs.

Fig. 2. Plasma concentrations-time curves (mean + S.D.) of *R*-warfarin or *S*-warfarin in hmEMs (*R*-; open circles, *S*-; open square) and PMs (*R*-; closed circles, *S*-; closed square)

Omeprazole 20 mg/daily was given orally to 17 healthy volunteers for 11 days, and on day

The pharmacokinetic parameters are summarized in Table 1. In hmEMs, the omeprazole treatment significantly increased *R*-warfarin AUC0-∞ (*P* = 0.004), and prolonged its t1/2 (*P* = 0.017) without any effect on *R*-warfarin Cmax or tmax. However, the omeprazole treatment did not alter any pharmacokinetic parameters of *S*-warfarin in both hmEMs and PMs as well as those of *R*-warfarin in hmEMs. Consequently, the omeprazole treatment decreased the *S*/*R* enantiomer ratio of warfarin AUC0-∞ from 0.51 to 0.43 in hmEMs (*P* = 0.010), but not in PMs. In addition, significant differences were found in mean Cmax (*P* < 0.001), t1/2 (*P* = 0.005), and AUC0-24 (*P* < 0.001) of omeprazole between different CYP2C19 genotypes, though there was no difference in mean Cmax or AUC0-24 of 5-hydroxyomeprazole between hmEMs and PMs.

**4. Drug interaction between omeprazole and warfarin enantiomers** 

7, a single dose of racemic warfarin 10 mg was added (Uno T et al., 2008).

after a single dose of 10 mg warfarin.


AUC, area under plasma concentration-time curve; Cmax, peak concentration; tmax, time to Cmax; t1/2, elimination half-life; CL, apparent oral clearance. The S/R ratios of AUC; AUC0-∞ *S*-warfarin / AUC0-<sup>∞</sup> *<sup>R</sup>*-warfarin. The metabolic ratio; AUC0-∞ of *S*-7-hydroxywarfarin / AUC0-∞ of *<sup>S</sup>*-warfarin. \* *P* <0.05,\*\**P <*0.01, \*\*\**P* <0.001*,* between hmEMs and PMs., **†***P* <0.05,**††***P* <0.01, between control and omeprazole phase. Data are shown as mean and 95% confidence interval ; tmax and fold change data are shown as a median wich a range.

Table 1. The summary of pharmacokinetics of warfarin enantiomers

## **5. Pharmacodynamics of warfarin**

No significant difference was found between hmEMs and PMs in either the PT-INR AUC0- 120 or the PT-INR max during the placebo phase, and the omeprazole treatment did not affect these parameters in both hmEMs and PMs (Uno T et al., 2008).
