PubMed Health⌕ Search

Biomedical subjects

Toshiro Niwa

Publications and source records attributed to Toshiro Niwa.

At least 19 recordsLinked to original sources
PubMed2007

Effect of cyclosporine and tacrolimus on cytochrome p450 activities in human liver microsomes.

The effects of cyclosporine and tacrolimus on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6beta-hydroxylation activities in human liver microsomes were compared. Cyclosporine and tacrolimus, at concentrations of 0.2 or 2 muM, neither inhibited nor stimulated any of the metabolic activities except for those of CYP3A4. On the other hand, cyclosporine and tacrolimus competitively inhibited CYP3A4-mediated nifedipine oxidation activity, with inhibition constants (K(i)) of 1.42 and 0.36 muM, respectively. In addition, 20 muM cyclosporine inhibited CYP2C19 and CYP2D6 activities by 29% and 30%, respectively. These results suggest that tacrolimus would not cause clinically significant interactions with other drugs, which are metabolized by CYPs, via the inhibition of hepatic metabolism and that the reason why cyclosporine, but not tacrolimus, has a pharmacokinetic inhibitory effect might be that the dosage and/or the unbound concentrations around its metabolic enzymes are higher than those of tacrolimus, rather than the differences in the inhibition potential. Obvious substrate-dependent effects on CYP3A4-inhibition potential were not observed.

Cells, Cultured↗
PubMed2006

Effects of serotonin-3 receptor antagonists on cytochrome P450 activities in human liver microsomes.

The effects of three serotonin-3 (5-HT(3)) receptor antagonists, azasetron, ondansetron, and ramosetron, on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6beta-hydroxylation activities in human liver microsomes were compared. Azasetron and ramosetron at a concentration of 1 or 10 muM neither inhibited nor stimulated any of the metabolic activities. On the other hand, ondansetron competitively inhibited CYP1A2 and CYP2D6 activities, and the inhibition constants (K(i)) were 3.2 and 21.0 muM, respectively, which are much higher than the reported plasma concentrations after clinical intravenous or oral dosing. The free fractions of the three 5-HT(3) receptor antagonists in the incubation mixture estimated by ultracentrifugation were more than 68.6%. These results suggest that azasetron, ondansetron, and ramosetron do not cause clinically significant interactions with other drugs that are metabolized by CYPs via the inhibition of metabolism.

Benzimidazoles↗
PubMed2006

[Development of new software (Ver. 2.0) based on the Bayesian estimation utilized in the therapeutic drug monitoring of teicoplanin, a glycopeptide antibiotic].

We developed a new software (Ver. 2.0) based on the Bayesian estimation utilized in the therapeutic drug monitoring (TDM) of teicoplanin, a glycopeptide antibiotic, for the estimation of individual pharmacokinetic parameters. Individual pharmacokinetic parameters were calculated by a least squares methods, MULTI2 (BAYES), and a two-compartment model with population pharmacokinetic parameters in adult patients in Japan was adopted. The predicted teicoplanin concentrations in patients were similar to the observed concentrations, suggesting that the software predicts with acceptable precision. This new software is now available in clinical practice.

Adult↗
PubMed2005

Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs.

The effects of micafungin on cytochrome P450 3A4 (CYP3A4) metabolic and multidrug resistance protein 1 (MDR1) transport activities were investigated and compared with those of amphotericin B and four azole antifungal drugs (ketoconazole, itraconazole, fluconazole and miconazole). The effects on the metabolic activity of CYP3A4 were examined by measuring nifedipine oxidase activity in human liver microsomes and the effects on MDR1 transport activity were evaluated using [3H]digoxin in MDR1-overexpressing LLC-GA5-COL150 cells. An inhibitory effect on CYP3A4 activity was found for ketoconazole, itraconazole and miconazole, with 50% inhibitory concentrations of 11.7, 32.6 and 74.2 nM, respectively. Fluconazole and micafungin had only slight inhibitory effects and amphotericin B had no effect. The MDR1-mediated transport of [3H]digoxin was inhibited by ketoconazole and itraconazole, and slightly by miconazole. It is suggested that micafungin and amphotericin B would be unlikely to cause drug-drug interactions by inhibition of CYP3A4 and MDR1. A positive correlation between the inhibitory effects on CYP3A4 and MDR1 activities was observed, and the physicochemical mechanisms involved and impact on clinical treatment should be studied further.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Interindividual variability in 5-Fluorouracil metabolism and procainamide N-acetylation in human liver cytosol.

We investigated the enzymatic kinetics and interindividual variability of the metabolism of 5-fluorouracil and procainamide by human liver cytosol and/or microsomes. The Km values for the 5-fluorouracil dihydropyrimidine dehydrogenase (DPD) and procainamide N-acetyltransferase activities in pooled liver cytosol, and procainamide hydrolysis in pooled liver microsomes were 3.9, 1670, and 969 microM, respectively, and the intrinsic clearance (Vmax/Km) values for these reactions were 128, 0.192, and 0.0059 microl/min/mg protein, respectively. The cytosolic activities of 5-fluorouracil metabolism and procainamide N-acetylation ranged from 145 to 790 (469+/-156, mean+/-S.D., n=22) and <1 to 152 (52+/-48, n=12) pmol/min/mg protein, respectively, and the DPD activity of 5-fluorouracil was neither gender-related nor age-dependent. Procainamide N-acetylation activities among 12 human cytosol samples were highly correlated with sulfamethazine N-acetylation activities, suggesting that procainamide N-acetylation is catalyzed by N-acetyltransferase-2. These results suggest that the N-acetylation reaction is more important than the hydrolysis in the metabolic pathway of procainamide, and that there are large interindividual differences in the enzyme activities towards the respective metabolic pathways of 5-fluorouracil and procainamide in human liver.

Acetylation↗
PubMed2005

Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs.

The metabolic activities of six psychotropic drugs, diazepam, clotiazepam, tofisopam, etizolam, tandospirone, and imipramine, were determined for 14 isoforms of recombinant human hepatic cytochrome P450s (CYPs) and human liver microsomes by measuring the disappearance rate of parent compounds. In vitro kinetic studies revealed that Vmax/Km values in human liver microsomes were the highest for tofisopam, followed by tandospirone>clotiazepam>imipramine, diazepam, and etizolam. Among the recombinant CYPs, CYP3A4 exhibited the highest metabolic activities of all compounds except for clotiazepam and imipramine. The metabolism of clotiazepam was catalyzed by CYP2B6, CYP3A4, CYP2C18, and CYP2C19, and imipramine was metabolized by CYP2D6 most efficiently. In addition, the metabolic activities of diazepam, clotiazepam, and etizolam in human liver microsomes were inhibited by 2.5 microM ketoconazole, a CYP3A4 inhibitor, by 97.5%, 65.1%, and 83.5%, respectively, and the imipramine metabolism was not detected after the addition of 1 or 10 microM quinidine, a CYP2D6 inhibitor. These results suggest that the psychotropic drugs investigated are metabolized predominantly by CYP3A4, except that CYP2D6 catalyzes the metabolism of imipramine. In addition, this approach based on the disappearance rate appears to be useful for the identification of the responsible CYP isoform(s) of older drugs, for which metabolic profiles have not been reported.

Biotransformation↗
PubMed2005

Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes.

The effects of five antifungal drugs, fluconazole, itraconazole, micafungin, miconazole, and voriconazole, on cytochrome P450 (CYP) 2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, and CYP3A4-mediated nifedipine oxidation activities in human liver microsomes were compared. In addition, the effects of preincubation were estimated to investigate the mechanism-based inhibition. The IC50 value against tolbutamide hydroxylation was the lowest for miconazole (2.0 microM), followed by voriconazole (8.4 microM) and fluconazole (30.3 microM). Similarly, the IC50 value against S-mephenytoin 4'-hydroxylation was the lowest for miconazole (0.33 microM), followed by voriconazole (8.7 microM) and fluconazole (12.3 microM). On the other hand, micafungin at a concentration of 10 or 25 microM neither inhibited nor stimulated tolbutamide hydroxylation and S-mephenytoin 4'-hydroxylation, and the IC50 values for itraconazole against these were greater than 10 microM. These results suggest that miconazole is the strongest inhibitor of CYP2C9 and CYP2C19, followed by voriconazole and fluconazole, whereas micafungin would not cause clinically significant interactions with other drugs that are metabolized by CYP2C9 or CYP2C19 via the inhibition of metabolism. The IC50 value of voriconazole against nifedipine oxidation was comparable with that of fluconazole and micafungin and higher than that of itraconazole and miconazole. The stimulation of the inhibition of CYP2C9-, CYP2C19-, or CYP3A4-mediated reactions by 15-min preincubation was not observed for any of the antifungal drugs, suggesting that these drugs are not mechanism-based inhibitors.

Antifungal Agents↗
PubMed2005

Effect of antifungal drugs on cytochrome P450 (CYP) 1A2, CYP2D6, and CYP2E1 activities in human liver microsomes.

The effects of five antifungal drugs, fluconazole, itraconazole, micafungin, miconazole, and voriconazole, on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2D6-mediated debrisoquine 4-hydroxylation, and CYP2E1-mediated chlorzoxazone 6-hydroxylation activities in human liver microsomes were compared. In addition, the effect of preincubation was estimated in order to investigate the mechanism-based inhibition. IC50 values of miconazole against CYP1A2 and CYP2D6 activities were 2.90 and 6.46 microM, respectively, and miconazole at 10 microM concentration slightly inhibited CYP2E1 activity. On the other hand, other antifungal drugs neither inhibited nor stimulated all of the metabolic activities. The stimulation of the inhibition of the metabolic activities mediated by CYP1A2, CYP2D6, or CYP2E1 by 15-min preincubation was not observed for any of the antifungal drugs, suggesting that these antifungal drugs are not mechanism-based inhibitors. These results suggest that miconazole is the strongest inhibitor against CYP1A2, CYP2D6, and CYP2E1 among the antifungal drugs investigated.

Antifungal Agents↗
PubMed2005

No inhibition of cytochrome P450 activities in human liver microsomes by sulpiride, an antipsychotic drug.

The effects of sulpiride, an antipsychotic drug, on cytochrome P450 (CYP) activities in human liver microsomes were investigated. Sulpiride at 50 or 500 microM concentration neither inhibited nor stimulated CYP1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, or CYP3A4-mediated testosterone 6beta-hydroxylation. The free fractions of sulpiride in the incubation mixture estimated by ultracentrifugation were more than 90.5%. These results suggest that sulpiride would not cause clinically significant interactions with other drugs, which are metabolized by CYPs, via the inhibition of metabolism.

Antipsychotic Agents↗
PubMed2005

[Drug-drug interaction of antifungal drugs].

This article reviews the in vitro metabolic and the in vivo pharmacokinetic drug-drug interactions with antifungal drugs, including fluconazole, itraconazole, micafungin, miconazole, and voriconazole. In the in vitro interaction studies, the effects of antifungal drugs on specific activities of cytochrome P450s (CYPs), including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, in human liver microsomes are compared to predict the possibility of drug interactions in vivo. Fluconazole, micafungin, and voriconazole have lower inhibitory effects on CYP3A4 activities than itraconazole and miconazole, and IC(50) and/or K(i) values against CYP2C9 and CYP2C19 activities are the lowest for miconazole, followed by voriconazole and fluconazole. In in vivo pharmacokinetic studies, it is well known that itraconazole is a potent clinically important inhibitor of the clearance of CYP3A4 substrates, and fluconazole and voriconazole are reported to increase the blood or plasma concentrations of not only midazolam and cyclosporine (CYP3A4 substrates) but also of phenytoin (CYP2C9 substrate) and/or omeprazole (CYP2C19/CYP3A4 substrate). On the other hand, no inhibition of CYP activities except for CYP3A4 activity by micafungin is observed in vitro, and the blood concentrations of cyclosporine and tacrolimus are not affected by coadministration of micafungin in vivo, suggesting that micafungin would not cause clinically significant interactions with drugs that are metabolized by CYPs via the inhibition of metabolism. Miconazole is a potent inhibitor of all CYPs investigated in vitro, although there are few detailed studies on the clinical significance of this except for CYP2C9. Therefore the differential effects of these antifungal drugs on CYP activities must be considered in the choice of antifungal drugs in patients receiving other drugs.

Antifungal Agents↗
PubMed2004

Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6.

Metabolic activities toward endogenous substrates in the brain, progesterone and p-tyramine, by cytochrome P450 2D6.2 (CYP2D6.2), CYP2D6.10A, CYP2D6.10C, and P34S, G42R, R296C, and S486T mutants expressed in recombinant Saccharomyces cerevisiae were compared with those by CYP2D6.1 (wild-type) in order to clarify the effects of genetic polymorphism of CYP2D6 on the metabolism of neuroactive steroids and amines in the brain. For the 6beta-hydroxylation of progesterone, the V(max) values for CYP2D6.2, CYP2D6.10A, and the P34S and G42R mutants, were less than half of those for CYP2D6.1, and CYP2D6.10C had a higher K(m) and a lower V(max) than the wild-type. The V(max)/K(m) values for CYP2D6.10A, CYP2D6.10C, and the P34S and G42R mutants were 12-31% of that for CYP2D6. The 16alpha-hydroxylation and 21-hydroxylation of progesterone by CYP2D6.10A, CYP2D6.10C, and the P34S and G42R mutants were not detected, and the R296C mutant had a higher K(m) for the 16alpha-hydroxylation and a lower V(max) for the 21-hydroxylation than those for CYP2D6.1. For dopamine formation from p-tyramine, the K(m) values for CYP2D6.2 and the R296C mutant were higher than those for CYP2D6.1, CYP2D6.10A, and CYP2D6.10C had a higher K(m) and a lower V(max) than the wild-type. The V(max)/K(m) values for CYP2D6.2, CYP2D6.10A, CYP2D6.10C and the P34S, G42R and R296C mutants were less than 45% of those for the wild-type. These results suggest the possibility that the polymorphism of CYP2D6, including CYP2D6*2, CYP2D6*10 and CYP2D6*12, might affect an individual behavior and the central nervous system through endogenous compounds, such as neuroactive steroids and tyramine, in the brain.

Adrenergic Uptake Inhibitors↗
PubMed2004

Tissue distribution after intravenous dosing of micafungin, an antifungal drug, to rats.

The tissue distribution after an intravenous dose of micafungin (1 mg/kg), a new echinocandin-like lipopeptide antifungal agent, to male rats was investigated. Micafungin in plasma disappeared biexponentially with a terminal half-life of 5.03 h. Micafungin concentrations in liver, kidney, and lung at the first sampling time (5 min) after dosing were 1.15, 1.64, and 2.58-fold higher than the plasma concentration, and the AUC(0- infinity ) were 1.61, 3.42, and 2.89-fold higher than that for plasma. The terminal half-lives for these tissues were 5.14, 4.87, and 5.31 h, respectively, which were comparable to those for plasma. These results suggest that micafungin distributes rapidly and moderately into tissues such as the liver, kidney, and lungs, and that the concentrations in tissues decreased in parallel with the unchanged drug in plasma.

Animals↗
PubMed2004

Interindividual variability in 2-hydroxylation, 3-sulfation, and 3-glucuronidation of ethynylestradiol in human liver.

In the current study, we investigated interindividual variability of the 2-hydroxylation, 3-glucuronidation, and 3-sulfation of ethynylestradiol (EE2) using human liver microsomes and cytosol. Km values for the 2-hydroxylation and 3-glucuronidation in pooled liver microsomes and for the 3-sulfation in pooled liver cytosol were 3.34, 23.3, and 2.85 microM, respectively. Vmax/Km (ml/min/g liver) was highest for the 3-sulfation, followed by 2-hydroxylation, suggesting that 3-sulfation is the major metabolic pathway of EE2 in human liver. All further studies were performed at a substrate concentration of 0.1 microM. Microsomal 2-hydroxylation and 3-glucuronidation activities ranged from 0.21 to 5.02 (2.04+/-1.34, mean+/-S.D., n=35) and 0.20 to 4.84 (1.20+/-1.00, n=35) pmol/min/mg protein, respectively. Cytosolic 3-sulfation activity ranged from 4.2 to 24.3 (11.8+/-4.4, n=21) pmol/min/mg protein. All the measured enzyme activities were neither gender-related nor age-dependent, except that 2-hydroxylation was significantly higher in females than in males (p<0.05). The relative contribution of CYP3A to the 2-hydroxylation in liver microsomes was estimated from the degree of inhibition by 1 microM ketoconazole. The degrees of inhibition were between 17.8 and 78.0% (51.6+/-16.0%, n=27). These results indicate that there are large interindividual differences in the enzyme activities towards the respective metabolic pathways of EE2 and the relative contribution of CYP3A to the 2-hydroxylation of EE2 in human liver.

Adolescent↗
PubMed2004

Effect of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 activities in human hepatic microsomes.

The effects of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 (CYP) activities in human hepatic microsomes were investigated. Nilvadipine competitively inhibited CYP1A2-mediated 7-ethoxyresorufin O-deethylase, CYP2A6-mediated coumarin 7-hydroxylase, CYP2C8/9-mediated tolbutamide methylhydroxylase, CYP2C19-mediated S-mephenytoin 4'-hydroxylase, and CYP3A4-mediated nifedipine oxidase activities, and the inhibition constant (Ki) values were 13.0, 35.8, 5.02, 24.5 and 44.3 microM, respectively. On the other hand, no inhibition of CYP2B6-mediated 7-benzyloxyresorufin O-debenzylation, CYP2D6-mediated bufuralol 1'-hydroxylation, or CYP2E1-mediated chlorzoxazone 6-hydroxylation by nilvadipine at 40 microM concentration was observed. The free fractions of nilvadipine in the incubation mixture estimated by ultracentrifugation were 18.9-27.4%. These results suggest that nilvadipine would not cause clinically significant interactions with other drugs, which are metabolized by CYPs, via the inhibition of metabolism.

Calcium Channel Blockers↗
PubMed2004

Effect of cefixime and cefdinir, oral cephalosporins, on cytochrome P450 activities in human hepatic microsomes.

The effects of two kinds of oral cephalosporins, cefixime and cefdinir, on cytochrome P450 (CYP) activities in human hepatic microsomes were investigated. Both cefixime and cefdinir at 2 mM concentration neither inhibited nor stimulated CYP1A1/2-mediated 7-ethoxyresorufin O-deethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated 7-benzyloxyresorufin O-debenzylation, CYP2C8/9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated bufuralol 1'-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, or CYP3A4-mediated testosterone 6beta-hydroxylation. The free fractions of cefixime and cefdinir in the incubation mixture, which were measured by ultracentrifugation, were 86.1-93.8% and 94.1-97.8%, respectively. These results suggest that both cefixime and cefdinir would not cause clinically significant interactions with other drugs, which are metabolized by CYPs, via the inhibition of metabolism.

Biotransformation↗
PubMed2004

[Development of software for data analysis by therapeutic drug monitoring of teicoplanin, a glycopeptide antibiotic].

We developed a new software named TEICTDM based on the Bayesian estimation utilized in the therapeutic drug monitoring (TDM) of teicoplanin, a glycopeptide antibiotic, for the estimation of individual pharmacokinetic parameters. Therefore, it is necessary to input more than one plasma concentration(s) determined in individual patient. Individual pharmacokinetic parameters were calculated by a least squares methods, MULTI2 (BAYES). Two-compartment model was applied to determine individual pharmacokinetic parameters in male healthy volunteers in Japan, and the relationship between clearance of teicoplanin and creatinine clearance in adult patients with various degrees of renal impairment in Europe was used. A series of work from data input to graph drawing or printing of results could efficiently carried out with the best of use of this software, suggesting that this software is now available in clinical practice.

Adult↗