Carvedilol is a b-adrenoceptor antagonist used clinically to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1-4) Carvedilol is highly lipophilic and eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.5) The drug is absorbed rapidly from the gastrointestinal tract after oral administration; however, the amount of unchanged drug excreted in the feces was 23% of the administered dose probably because of incomplete intestinal absorption.6) In addition, orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low bblocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.6) The mean absolute bioavailability of R-and S-enantiomer in humans is 31% and 15%, respectively. 7)In the previous study, we investigated the effect of genetic polymorphisms of cytochrome P450 (CYP) 2D6 on the pharmacokinetics of R-and S-carvedilol in 23 healthy Japanese volunteers.8) The large interindividual variability was observed in the pharmacokinetics of carvedilol, and the coefficient of variation of the weight (WT)-corrected oral clearance ((CL/F)/ WT) value among the subjects was 36.1%. In addition, the (CL/F)/WT value was highly correlated with the apparent distribution volume ((V/F)/WT) value among the subjects, suggesting that the interindividual difference in bioavailability (F) was at least partly responsible for the pharmacokinetic variability of carvedilol. The (CL/F)/WT and (V/F)/WT values of R-and S-carvedilol were significantly lower in healthy volunteers with at least one CYP2D6*10 allele than those with the CYP2D6*1/*1 and *1/*2 genotype. The result suggested that the systemic and/or pre-systemic metabolism of R-and S-carvedilol in the liver is significantly decreased in Japanese subjects with the CYP2D6*10 allele.Carvedilol is metabolized extensively via aliphatic sidechain oxidation and conjugation pathways, as well as the aromatic ring oxidation pathway which is mediated mainly by CYP2D6. 6) Oldham et al. reported that considerable metabolic activity for carvedilol is observed in CYP1A2, 2C9, 2D6, and 3A4. 9) On the other hand, it is still unclear whether the other P450s are involved in the metabolism of carvedilol. However, a substrate of CYP2C9, such as phenytoin, is partly catalyzed by another CYP2C subfamily, CYP2C19. 10)CYP3A5 is another important CYP3A protein in the liver, the substrate specificity of which largely overlaps with that of CYP3A4.11) In addition, Ohno et al. reported that UDP-glucuronosyltransferase (UGT) 1A1, 2B4, and 2B7 as well as human hepatic microsomes are capable of catalyzing the glucuronidation of carvedilol.12) Moreover, carvedilol has high affinity for the multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp). Giessmann et al. reported that the intestinal expression of P-gp is a major variable in the disposition of carvedilol. 13)In the presen...

This study was performed to estimate the mean pharmacokinetic parameters of routinely administered metoprolol in middle-aged and elderly Japanese patients. Whole blood concentration data (65 samples) at steady-state following repetitive administration to 34 patients were analyzed using a nonlinear mixed effects model. A one-compartment model was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F). We evaluated the effect of polymorphic alleles (CYP2D6*2, CYP2D6*10, CYP2C19*2 and CYP2C19*3), age, gender, and heart failure on the pharmacokinetic parameters of metoprolol. The CL/F value in patients homozygous for the CYP2D6*10 allele was 64% lower than that in patients with a CYP2D6*1/*1 or *1/*2 genotype. The CL/F value in older (Ͼ70 years old) patients was 26% lower than that in younger (Յ70 years old) patients. In addition, the V/F value in patients homozygous for the CYP2D6*10 allele was 25% lower than that in patients with the CYP2D6*1/*1 or *1/*2 genotype. On the other hand, the CYP2C19 genotype, gender, and heart failure showed no significant effects on the pharmacokinetics of metoprolol. The results suggest that the pharmacokinetic variability of metoprolol in Japanese extensive metabolizers of CYP2D6 is very large, probably because CYP2D6*10 is responsible not only for the decreased systemic clearance (CL) but also for the increased bioavailability (F) of the drug.

Carvedilol is a b-adrenoceptor antagonist, and has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias. [1][2][3][4] Carvedilol is highly lipophilic and eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.5) The drug is absorbed rapidly from the gastrointestinal tract after oral administration; however, the amount of unchanged drug excreted in the feces was 23% of the administered dose probably because of incomplete intestinal absorption.6) In addition, orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.6) The mean absolute bioavailability of R-and S-enantiomer in humans is 31% and 15%, respectively. 7)It was reported that CYP2D6 in microsomes derived from lymphoblastoid cells with human cDNA shows strong enzyme activity for the metabolism of R-and S-carvedilol. 8)Poor metabolism through CYP2D6 was found in 7% of Caucasian subjects, and two common defective alleles responsible for the poor metabolism are CYP2D6*4 and *5.9) The gene frequency of individual variants of CYP2D6 shows a marked interethnic difference, and poor metabolism is found in less than 1% of Asian subjects. 9) Among Asian extensive/ intermediate metabolizers, the three most common alleles of the CYP2D6 gene are CYP2D6*1, *2, and *10. The mutant allele of CYP2D6 (CYP2D6*2) does not affect the enzyme activity, whereas the CYP2D6*10 allele causes the low expression and affinity of CYP2D6. 10,11) In the present study, we estimated the pharmacokinetic parameters of R-and S-carvedilol in 23 healthy Japanese volunteers by the Bayesian method using a nonlinear mixed effects model (NONMEM) program. We then examined the effect of the CYP2D6 polymorphisms on the stereoselective pharmacokinetics of carvedilol. MATERIALS AND METHODS Subjects and Study ProtocolsTwenty-three healthy Japanese volunteers (19 men and 4 women) participated in this study. The age was between 22 and 44 years old (mean: 29.1), and the body weight was between 47 and 86 kg (mean: 64.7). They were given 5 mg (two 2.5 mg-tablets: 7 men and 2 women) or 10 mg (one 10 mg-tablet: 12 men and 2 women) of carvedilol (Artist ® tablet; Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan) at least 2 h before a meal, because the peak blood drug concentrations are attained at 0.5-1 h after oral administration following an over night fast.12) Carvedilol was taken with a glass of water, and 5 ml of blood was taken at 2 and 6 h after dosing. All the subjects were physicians or pharmacists, and they chose the dose of carvedilol by themselves. The mean (ϮS.D.) body weight in the subjects taking 5 mg and 10 mg carvedilol was 57.9Ϯ6.7 kg and 69.1Ϯ 9.9 kg, respectively. They all gave written consent to participate in this study, which was approved by the ethics committee of Toyama Medica...

In patients routinely treated with metoprolol, influences of CYP2D6 genotype on the response of heart rate to isoproterenol (IP) were studied at its peak and trough concentrations and were compared with those of bisoprolol. In 72 patients treated with metoprolol or bisoprolol, CYP2D6 genotype (ie, CYP2D6*1, *2, *4, *5, *10, and *14) was determined. No patients except one who was heterozygous for CYP2D6*5 carried the null alleles of CYP2D6. The homozygote frequency for CYP2D6*10 was relatively high (19.4%) and these patients had greater peak and trough plasma concentrations of metoprolol than the other patients. Isoproterenol-induced percentage increases in heart rate were 58% and 38% less at the low and high rate of isoproterenol infusion (0.02 and 0.04 microg/kg/min), respectively, in patients homozygous for CYP2D6*10 than in the other patients at the trough, but not at the peak concentrations. In contrast, CYP2D6 genotype did not affect plasma concentrations of bisoprolol and the extent of its beta-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant beta-adrenergic inhibition independent of CYP2D6 genotype.

The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42-19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose and the therapeutic prothrombin time-international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients.