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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...

To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma S-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of S-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC50. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that CYP2C9*3 mutation and body surface area were predictors of CL(S), that VKORC1 and CYP4F2 polymorphisms were predictors of IC50, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.Trial RegistrationClinicalTrials.gov NCT02065388

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ABSTRACT:Verapamil (VP) is used as a racemate but shows stereoselective pharmacokinetics and pharmacodynamics. It undergoes extensive first-pass metabolism. Stereoselective first-pass metabolism in the intestine and liver was investigated in vivo and in vitro to determine its impact on the disposition of VP and its main metabolite, norverapamil (NVP). VP racemate was administered to rats i.v., p.o., and via the portal vein. The formation rates of the main metabolites of the VP enantiomers were estimated in an in vitro intestinal microsomal study. The hepatic bioavailability of VP showed saturable metabolism, and the hepatic bioavailability of R-VP was higher than that of S-VP. Conversely, the intestinal bioavailability of R-VP was lower than that of S-VP, resulting in a higher systemic bioavailability of S-VP. The pharmacokinetics of the NVP enantiomers was similar. These results suggest that the stereoselectivity of the total bioavailability of VP is determined by first-pass metabolism in the small intestine and liver, and that the NVP enantiomers observed in the systemic circulation after p.o. administration of VP racemate originate mainly from the liver in rats.The first-pass metabolism of drugs in the small intestine and liver limits their bioavailability to the systemic circulation. Although the effects of first-pass metabolism in the liver after p.o. administration have been well studied, it is now known that many drugs also undergo first-pass metabolism in the small intestine. Reductions in the firstpass metabolism of these drugs, caused by drug-drug interactions or disease states, may occur to a different extent in the small intestine and liver. Therefore, it is very important to elucidate the mechanisms underlying first-pass metabolism, as well as the separate contributions of metabolism in the small intestine and liver, to be able to predict changes in oral bioavailability.Verapamil (VP) is a calcium antagonist used clinically for the treatment of hypertension and for prophylaxis of supraventricular and ventricular arrhythmias. VP has a relatively narrow therapeutic plasma concentration range and shows relatively large interindividual variations in its pharmacokinetics and pharmacodynamics (Vogelgesang et al., 1984;Echizen et al., 1985a Echizen et al., ,b, 1988. Although VP is commercially available as a racemic mixture, its pharmacological effects and disposition have been reported to show stereoselectivity in both humans and animals. The antiarrhythmic effect of S-VP, as estimated by electrocardiograph, is 10 to 20 times higher than that of R-VP in humans (Echizen et al., 1985a,b). The oral bioavailability of S-VP is approximately 20% in humans, whereas that of R-VP is approximately 50% (Vogelgesang et al., 1984;Echizen et al., 1985a Echizen et al., ,b, 1988. The plasma protein binding of R-VP is higher than that of S-VP (free fractions: 7 and 12%, respectively) (Gross et al., 1988;Robinson and Mehvar, 1996). We have previously reported that VP binds enantioselectively to ␣1-acid glycoprotein and ...