The ethnic difference in warfarin maintenance dose was mainly dependent on the linked VKORC1 variants. Genotyping of -1639 G>A of the VKORC1 gene could be clinically important for predicting individual variability in anticoagulant responses to warfarin.

Carvedilol is an b 1 , b 2 and a 1 adrenergic receptor antagonist, clinically administered as a racemic mixture of the R(ϩ)-and S(Ϫ)-enantiomers. Beta-blockers have been reported to prolong life and reduce the risk of disease progression in patients with chronic heart failure (CHF).1-3) However, these drugs have a risk of causing symptomatic hypotension and/or worsening heart failure during the dose titration step. As tolerance to treatment with carvedilol varies widely among individuals, careful titration and treatment initiation are necessary in daily practice. The pharmacokinetics of carvedilol and its covariates in patients with CHF have been investigated, 4,5) but the relationship between pharmacokinetics and tolerability, and the cause of this wide inter-individual variability, are still unclear.The R-and the S-enantiomers of carvedilol exhibit different pharmacological effects, i.e., the b-receptor blocking activity of S-carvedilol is about 200 times higher than that of R-carvedilol, whereas both enantiomers are equipotent ablockers.6) Also, the enantiomers exhibit differences in pharmacokinetic behavior in humans. 7,8) Carvedilol is metabolized to various derivatives by both oxidation and conjugation in the liver, and the main oxidative isoenzyme is cytochrome P450 (CYP) 2D6. 9) Absolute bioavailability upon oral administration is 31.1% and 15.1% for the R-and Senantiomers, respectively, and the difference in metabolic stability is attributed mainly to CYP2D6.10,11) Carvedilol shows high plasma protein binding (98-99%), 12) and is known to bind to a 1 -acid glycoprotein with high affinity. 13)The COMMET study reported that serious adverse and CHF-related events in patients switching from metoprolol (a b 1 -selective agent) to carvedilol (a nonselective agent) were lower than in patients switching from carvedilol to metoprolol.14) It is considered that the vasodilation effect through a 1 blockade and its potency might be a key factor in b-blocker tolerability. Therefore, it is very important to assess the characteristics of enantioselective pharmacokinetics, and clarify the factors that influence clinical response.In this study, we investigated the population pharmacokinetic parameters of R-and S-carvedilol and its covariates in Japanese patients with CHF, and evaluated the effect of CYP2D6 genotypes on individual oral clearance (CL/F) values. Relationships between adverse events and drug exposure level were also assessed by exploratory analysis. Research." These protocols were approved by the institutional review board of Sakakibara Heart Institute. Written informed consent for participation in the study was obtained from all patients. Studies I and II had the same inclusion and exclusion criteria. The main demographic characteristics are presented in Table 1. The patients ranged in age from 31 to 87 years (mean: 65 years), with a body weight of between 33.8 and 94.0 kg (mean: 58.5 kg). Carvedilol is a b-adrenoceptor antagonist used for treating chronic heart failure (CHF). Two clinical studies were cond...

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