Masato Taguchi

Effect of the VKORC1 Genotype on Warfarin Dose Requirements in Japanese Pediatric Patients

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.

Pharmacokinetics of Bosentan in Routinely Treated Japanese Pediatric Patients with Pulmonary Arterial Hypertension

We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.

Bosentan induces clinical and hemodynamic improvement in candidates for right-sided heart bypass surgery

OBJECTIVEnTo investigate the efficacy of bosentan in patients with single-ventricle physiology who were unable to undergo right-sided heart bypass surgery because of high pulmonary vascular resistance and pulmonary artery pressure.nnnMETHODSnEight patients with single-ventricle physiology (2 male and 6 female; aged 7 months to 5 years, median 1 year) were enrolled. Prior surgical interventions included pulmonary artery banding in 4 patients, Blalock-Taussig shunt operation in 2 patients, and bidirectional Glenn operation in 5 patients. Right-sided heart bypass surgery was contraindicated for all patients because of high pulmonary vascular resistance and pulmonary artery pressure.nnnRESULTSnBosentan therapy successfully reduced pulmonary artery pressure and pulmonary vascular resistance in all patients. Mean pulmonary artery pressure at baseline and after bosentan therapy was 21.1 +/- 7.2 mm Hg and 11.9 +/- 4.1 mm Hg, respectively (P < .01). Mean pulmonary vascular resistance index at baseline and after bosentan therapy was 5.7 +/- 3.3 U/m(2) and 1.3 +/- 0.4 U/m(2), respectively (P < .01). Mean pulmonary vascular resistance/systemic vascular resistance at baseline and after bosentan therapy was 0.25 +/- 0.11 and 0.07 +/- 0.03, respectively (P < .01). All patients had improved clinical symptoms and underwent successful Fontan operations.nnnCONCLUSIONnBosentan induces mid-term clinical and hemodynamic improvement in patients with single-ventricle physiology and elevated pulmonary vascular resistance and pulmonary artery pressure. Bosentan therapy may increase the surgical options and improve outcomes in candidates for right-sided heart bypass surgery.

Mechanisms for membrane transport of metformin in human intestinal epithelial Caco-2 cells.

The aim of the present study was to investigate the mechanisms for membrane transport of metformin in human intestinal epithelial Caco‐2 cells. The mRNA of not only organic cation transporter (OCT) 3, but also OCT1 and OCT2, was expressed in Caco‐2 cells. The uptake of 100u2009µm metformin at the apical membrane of Caco‐2 cells grown on porous filter membrane was significantly greater than that at the basolateral membrane. The apical uptake of 100u2009µm metformin in Caco‐2 cells grown on plastic dishes was inhibited significantly by 1u2009mm unlabeled metformin, quinidine and pyrilamine, indicating that a specific transport system is involved in the apical uptake of metformin in Caco‐2 cells. The apical uptake of 100u2009µm metformin in Caco‐2 cells was decreased by acidification of the medium, but not increased by alkalization. In addition, carbonyl cyanide 4‐(trifluoromethoxy)phenylhydrazone (a protonophore) had no effect on the apical uptake of metformin in Caco‐2 cells at apical medium pH 8.4. These findings suggested that the apical uptake of metformin in Caco‐2 cells is mediated at least partly by OCTs, but that the postulated H+/tertiary amine antiport system is not responsible for the apical uptake of metformin. Copyright

Mechanisms responsible for the altered pharmacokinetics of bosentan: analysis utilizing rats with bile duct ligation-induced liver dysfunction.

The purpose of this study was to evaluate the mechanisms responsible for the pharmacokinetic variability of bosentan utilizing rats with liver dysfunction induced by 7‐day bile duct ligation (BDL). Bosentan was administered intravenously at a constant infusion rate (I) of 24, 40 or 60u2009µg/min/kg. The blood bosentan concentration (BBC) following infusion was measured by HPLC, and apparent clearance (CL) of the drug was estimated as I/BBC. The CL values in normal rats were 30.5 and 19.3u2009ml/min/kg at infusion rates of 24 and 60u2009µg/min/kg, respectively, suggesting non‐linear pharmacokinetics of bosentan. The BBC in BDL rats was much higher than that in normal rats, and the CL values in BDL rats were 3.80 and 3.08u2009ml/min/kg at infusion rates of 24 and 60u2009µg/min/kg, respectively. The CL value of bosentan at an infusion rate of 40u2009µg/min/kg in normal rats was decreased significantly by the coadministration of taurocholic acid or bilirubin. In addition, the hepatic mRNA expression of CYP2C6, CYP3A2, Oatp1a1, Oatp1a4 and Oatp1b2 in BDL rats decreased to 77.6%, 34.0%, 65.4%, 84.8% and 44.2% of that in normal rats, respectively. These results suggested that bile acids and/or bilirubin accumulated in BDL rat plasma inhibited the hepatic uptake of bosentan, and that the decreased bosentan clearance in BDL rats was caused at least partly by the impaired expression of hepatic drug‐metabolizing enzymes and uptake transporters. Moreover, because the pharmacokinetics of bosentan was non‐linear at the tested doses, the increased BBC in BDL rats might further induce the saturation of hepatic uptake and/or metabolism of bosentan. Copyright