The aim of the present study was to investigate the genetic factors responsible for the interindividual variability in the bioavailability of mizoribine. Thirty healthy Japanese men aged 20-49 years and weighing 53-75 kg participated in the present study and took 150 mg of mizoribine. Urine samples were collected periodically for 12 h after the dose, and the bioavailability of mizoribine was calculated from the estimated total urinary excretion from time zero to infinity. The bioavailability of mizoribine in the 30 subjects ranged from 60.3% to 99.4%. The mean bioavailability of mizoribine in subjects with the concentrative nucleoside transporter 1 (SLC28A1) 565-A/A allele (75.4%) was significantly lower than that in subjects with the SLC28A1 565-G/G allele (90.1%). On the other hand, the bioavailability of mizoribine was not affected by polymorphisms of breast cancer resistance protein (ABCG2) C421A and multidrug resistance-associated protein 4 (ABCC4) G2269A. The findings in the present prospective study suggested that the genetic test for the SLC28A1 G565A polymorphism is promising for predicting the Japanese subjects with lower bioavailability of mizoribine.
We previously reported that aging and/or cytochrome P450 2D6 polymorphism are responsible for the interindividual variability in the systemic clearance (CL) and bioavailability (F) of metoprolol. The aim of the present study was to evaluate the residual variability of F of metoprolol in routinely treated Japanese patients and to investigate the intestinal absorption mechanism of the drug using human intestinal epithelial LS180 cells. We first re-analyzed the blood concentration data for metoprolol in 34 Japanese patients using a nonlinear mixed effects model. The oral clearance (CL/F) of metoprolol was positively correlated with the apparent volume of distribution (V/F), suggesting the residual variability of F. The uptake of metoprolol into LS180 cells was significantly decreased by the acidification of extracellular medium pH, and was dependent on temperature and intracellular pH. Furthermore, the cellular uptake of metoprolol was saturable, and was significantly decreased in the presence of hydrophobic cationic drugs such as diphenhydramine, procainamide, bisoprolol, and quinidine. These findings indicate that residual variability of F is one of the causes of the interindividual pharmacokinetic variability of metoprolol, and that the interindividual variability of not only presystemic first-pass metabolism, but also intestinal absorption, may be responsible for the variable F of the drug.
Heart failure is accompanied with tissue (circulatory) hypoxia, and the metabolism of several drugs has been reported to be reduced in heart failure. The aim of this study was to investigate the effect of another type of respiratory hypoxia, hypoxic hypoxia (FiO2 15 % for 24 h followed by FiO2 10 % for 9 days) on the metabolism of carvedilol enantiomers in rats. Oxidation of carvedilol in rat liver microsomes was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Both oxidation and glucuronidation activities for two carvedilol enantiomers in hypoxic rat liver microsomes were similar to those in control rat liver microsomes. We also performed pharmacokinetic analysis of carvedilol enantiomers following intraportal infusion in control and hypoxic rats. The mean (±S.E.) portal clearance value of R- and S-carvedilol in control rats was 72 ± 16 and 156 ± 31 ml/min/kg, respectively, whereas that of the R- and S-enantiomers in hypoxic rats was 68 ± 8 and 113 ± 14 ml/min/kg, respectively. These findings indicated that the metabolism of carvedilol enantiomers was not significantly diminished in rats with chronic hypoxic hypoxia, and that other factor(s) besides hypoxia may be responsible for the reduced drug metabolism in heart failure.
We previously reported that there is a positive correlation between the oral clearance (CL/F) and the apparent volume of distribution (V/F) of drugs with variable bioavailability (F). The aim of the present study using the computer simulation method was to further evaluate the usefulness of the population pharmacokinetic analysis model assuming the covariance of CL/F and V/F (ωCL/F, V/F). The log likelihood difference (LLD) between the covariance and noncovariance model analysis was weakly altered by the change of the inter-individual difference of volume of distribution (V) and systemic clearance (CL), and was slightly altered by the change of intra-individual error of blood concentration measurement. The LLD was also weakly altered by the change of the blood sampling design and by the number of subjects in clinical trials. In contrast, the LLD was significantly affected by the change of the range of F. However, the LLD value for the clinical trial of the drug with 80-100% of F was still statistically significant. Therefore, we should use the covariance model for the population pharmacokinetic analysis for drugs with mean F below 80%.
The large variability of the bioavailability (F) of mizoribine accelerates the positive correlation between the apparent volume of distribution (V/F) and the oral clearance (CL/F). The aim of the present study was to assess whether the variable F of mizoribine in healthy adult men is one of the factors in the interindividual pharmacokinetic variability of the drug. The serum concentration data of mizoribine were analyzed by the nonlinear mixed effects model program with first-order (FO), first-order conditional estimation (FOCE), and Laplacian methods. The 1-compartment model with absorption lag time and first-order absorption fitted well with healthy adult data, and there was a significant positive correlation between V/F and CL/F. The performance of FO method analysis for adult data was deteriorated considerably by misspecification of the random effect, whereas the FOCE method was robust for model misspecification. On the other hand, the performance of FOCE method analysis for the data obtained from pediatric patients with renal diseases was inferior to that of quasi-gold-standard Laplacian method analysis, probably because of the flip-flop problems in the conditional (Bayesian) estimation step of the FOCE analysis. The present findings confirm that F of mizoribine is variable in the healthy adult population, and also suggest that conditional estimation (FOCE and Laplacian) methods should be utilized positively and carefully while considering their advantages and disadvantages.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.