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The purpose of this study was to evaluate the pharmacokinetics of R- and S-carvedilol in routinely treated Japanese patients with heart failure. We measured peak and trough blood concentrations at steady state following repeated oral administration to 24 patients. The blood concentration of S-carvedilol with potent beta-blocking activity was lower than that of R-carvedilol. The mean oral clearance (CL/F) of R- and S-carvedilol was not altered by CYP2D6*10, UGT2B7*3, and the etiology of heart failure. In addition, the CL/F values of enantiomers were not correlated with age, creatinine clearance, and plasma concentrations of alpha1-acid glycoprotein and brain natriuretic peptide. On the other hand, the mean CL/F values of R- and S-carvedilol in patients with heart failure were 0.89 and 1.52 l/h/kg, respectively, considerably lower than those estimated previously in healthy subjects. These results suggested that the pharmacokinetics of R- and S-carvedilol was altered significantly by heart failure.

The aim of this study was to evaluate the pharmacogenetic variability in the disposition of carvedilol in the Japanese population. Five or 10 mg of carvedilol was orally administered to 54 healthy Japanese subjects (22-44 years old), and blood samples were taken at 2 and 6 h after dosing. We determined the polymorphic alleles of CYP2D6, CYP2C9, CYP2C19, CYP3A5, UGT2B7, and MDR1 in each subject. The whole blood concentration of R- and S-carvedilol was measured by an HPLC method. The pharmacokinetic parameters in individual subjects were estimated by the Bayesian method using the nonlinear mixed effects model (NONMEM) program. We then examined the effect of the genetic polymorphisms on the variability in the pharmacokinetics of carvedilol using a multiple regression analysis. The oral clearance (CL/F) and also apparent volume of distribution (V/F) of both enantiomers were significantly lower in the subjects with the CYP2D6*10 allele than those with the CYP2D6*1/*1, *1/*2, or *2/*2 genotype, confirming our previous finding that the bioavailability (F) and systemic clearance (CL) of R- and S-carvedilol in the liver is significantly altered in Japanese with the CYP2D6*10 allele. On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, and MDR1 C3435T did not significantly affect the pharmacokinetics of carvedilol in Japanese subjects.

The population pharmacokinetic parameters of mizoribine in healthy subjects were estimated using a nonlinear mixed effects model (NONMEM) program. Pharmacokinetic data for population analysis were obtained in the previous study, in which 24 healthy Caucasian male subjects participated in a single-dose (3, 6, 9, 12 mg/kg) study, and 12 subjects participated in a multiple-dose (6, 12 mg/kg/d) study. The mean value of the absorption lag time, absorption rate constant (KA), and apparent distribution volume (V/F) was estimated to be 0.349 h, 0.869 h-1, and 0.834 l/kg, respectively. Oral clearance (CL/F) was modeled with creatinine clearance (CLcr), and the mean value was estimated to be 1.93.CLcr l/h. In addition, pharmacokinetic parameters in individual 36 subjects were obtained from population estimates according to Bayes' theorem. Pharmacokinetic parameters (KA, V/F, and CL/F) in the single-dose study were almost constant at a dose range of 3-12 mg/kg, and were similar to those in the multiple-dose study. These findings indicated that the pharmacokinetics of mizoribine is well described by a simple one-compartment model with first-order absorption.

Summary: We previously investigated the pharmacokinetics of R- and S -carvedilol in 54 healthy Japanese subjects, and reported that the oral clearance ( CL / F ) and apparent volume of distribution ( V / F ) of both enantiomers in subjects with the CYP2D6 * 10 allele were significantly lower than those in subjects without the CYP2D6 * 10 allele. In the present study, we examined the genotype of UGT2B7 in these 54 subjects, and investigated the effect of UGT2B7 * 3 on the pharmacokinetics of R - and S -carvedilol. Forty-three subjects did not have the UGT2B7 * 3 allele, and 11 subjects had one UGT2B7 * 3 allele. CL / F and V / F values of R- and S-carvedilol in the subjects with one UGT2B7 * 3 allele were similar to those without the UGT2B7 * 3 allele, indicating that the UGT2B7 * 3 allele did not significantly affect the systemic clearance ( CL ) and bioavailability ( F ) of the two enantiomers.

This study was performed to investigate the effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers. Five or 10 mg of carvedilol was orally administered to 23 subjects (22-44 years old), and blood samples were taken at 2 and 6 h after dosing. We determined the polymorphic alleles of CYP2D6 in each subject. The whole blood concentration of R- and S-carvedilol was measured by an HPLC method. The pharmacokinetic parameters in individual subjects were estimated by the Bayesian method using the nonlinear mixed effects model (NONMEM) program. The mean values of oral clearance for R- and S-carvedilol were estimated to be 1.01 and 2.15 l/h/kg, respectively. The oral clearance was highly correlated with the apparent volume of distribution among the subjects, suggesting that the interindividual difference in bioavailability was largely responsible for the pharmacokinetic variability of carvedilol. The oral clearance and also volume of distribution of both enantiomers were significantly lower in the subjects with the CYP2D6*10 allele than with the CYP2D6*1/*1 or *1/*2 genotype. These results suggested that the systemic and/or pre-systemic metabolism of R- and S-carvedilol in the liver is significantly decreased in Japanese with the CYP2D6*10 allele.