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Biomedical subjects

O Okazaki

Publications and source records attributed to O Okazaki.

At least 55 records · Page 3Linked to original sources
PubMed1993

Evidence for specific base catalysis in N-dealkylation reactions catalyzed by cytochrome P450 and chloroperoxidase. Differences in rates of deprotonation of aminium radicals as an explanation for high kinetic hydrogen isotope effects observed with peroxidases.

Alkylamines are oxidized by a number of different types of enzymes, and the low oxidation potentials favor 1-electron transfer processes and aminium radicals. We studied the mechanism of N-dealkylation by hemoproteins using the prototypic substrate N,N-dimethylaniline (with isotopic substitution on the methyl groups), since there were considerable data available from kinetic deuterium isotope studies suggesting alternative mechanisms for different hemoproteins (Miwa, G.T., Walsh, J.S., Kedderis, G.L., and Hollenberg, P. F. (1983) J. Biol. Chem. 258, 14445-14449). Cytochrome P450 2B1 (P450), chloroperoxidase, and several biomimetic metalloporphyrin systems showed low kinetic hydrogen isotope effects (D(V/K)intra < or = 2.0, T(V/K) < or = 3.4), and hemoglobin, horseradish peroxidase, and prostaglandin H synthase yielded high isotope effects (D(V parallel K)intra > or = 3.5, T(V/K) > or = 8.1), in agreement with previous studies. Dinnocenzo and Banach (Dinnocenzo, J. P., and Banach, T. E. (1989) J. Am. Chem. Soc. 111, 8646-8653) have provided evidence that the pKa for an alpha-hydrogen of the N,N-dimethylaniline aminium radical is approximately 9 and also estimated that the pKa for the 4-hydrogen of a 1,4-dihydropyridine aminium radical is approximately 3.5. The oxidations of two model 1,4-dihydropyridines showed only low kinetic hydrogen isotope effects with all of the enzymes examined (D(V/K) < or = 2.3, T(V/K) < or = 2.8). Aminium radicals derived from aminopyrine and N,N-dimethylthioanisole accumulated only with those hemoprotein systems showing the high isotope effects with N,N-dimethylaniline. We conclude that specific base catalysis of alkyl hydrogen removal from aminium radicals by the (Fe.O)2+ complex is a feature of some hemoproteins, including P450s, and that the lack of such catalysis in other hemoproteins is the basis of their high kinetic hydrogen isotope effects.

Alkylation↗
PubMed1993

Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic.

The safety and pharmacokinetic properties of DQ-2556, a new parenteral cephalosporin, were evaluated using healthy volunteers after 5-minute intravenous infusion of doses of 250, 500, 1000, or 2000 mg and a 1-hour infusion of 2000 mg, and an intramuscular dose of 500 mg. The half-lives of DQ-2556 ranged from 1.64 to 2.15 hours. The peak serum concentrations and area under the curve values were linearly correlated to the doses. The mean urinary recoveries were 80.0 to 85.5% of a dose within 24 hours. Salivary concentrations of the drug were low. There was no accumulation of DQ-2556 after 9 administrations every 12 hours. DQ-2556 was well tolerated.

Adult↗
PubMed1993

Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide.

The mechanisms of reduction in absorption of levofloxacin (LVFX) by coadministration of aluminum hydroxide were studied. The partition coefficient of LVFX (0.1 mM) between chloroform and phosphate buffer (pH 5.0) was reduced by 60 to 70% with the addition of metal ions such as Cu2+, Al3+, and Fe2+ (0.8 mM), which indicated the formation of LVFX-metal ion chelates. However, there was no significant difference in absorption from rat intestine between the synthetic LVFX-Al3+ (1:1) chelate (6.75 mM) and LVFX (6.75 mM) in an in situ recirculation experiment. On the other hand, Al(NO3)3 (1.5 mM) significantly inhibited the absorption of LVFX (1.5 mM) by 20% of the control in the in situ ligated loop experiment, in which partial precipitation of aluminum hydroxide was observed in the dosing solution. Data for adsorption of LVFX and ofloxacin (OFLX) from aqueous solution by aluminum hydroxide were shown to fit Langmuir plots, and the adsorptive capacities (rmax) and the K values were 7.0 mg/g and 1.77 x 10(4) M-1 for LVFX and 7.4 mg/g and 1.42 x 10(4) M-1 for OFLX, respectively. The rate of adsorption of several quinolones (50 microM) onto aluminum hydroxide (2.5 mg/ml) followed the order norfloxacin (NFLX) (72.0%) > enoxacin (ENX) (61.0%) > OFLX (47.2%) approximately LVFX (48.1%). The elution rate of adsorbed quinolones with water followed the rank order LVFX (17.9%) approximately OFLX (20.9%) approximately ENX (18.3%) > NFLX (11.9%). These results strongly suggest that adsorption of quinolones by aluminum hydroxide reprecipitated in the small intestine would play an important role in the reduced bioavailability of quinolones after coadministration with aluminum-containing antacids.

Aluminum Hydroxide↗
PubMed1992

Possible effect of pigment on the pharmacokinetics of ofloxacin and its excretion in hair.

The mechanism of excretion of the antimicrobial ofloxacin in human scalp hair was investigated. When black and white hairs were taken from a patient with grizzled hair, who had been treated with ofloxacin, a much larger quantity of the drug was detected in the black hair. To study this difference and to elucidate the cause, ofloxacin (6, 20, and 60 mg/kg/day, b.i.d.) was administered ip for 5 weeks to albino and pigmented rats, whose backs had been depilated beforehand. In the last week of administration, the time-plasma concentration profile of ofloxacin was determined. One week after the last dosing, the newly grown hair on the depilated area was collected, and the drug concentration in hair was measured. The concentration in hair of the pigmented rats correlated significantly with the daily dose, area under the plasma concentration curve (AUC), and maximum plasma concentration (Cmax) at steady state, whereas that in the albino rats correlated with the dose and Cmax only, because AUC did not increase linearly with the dose in the albino rats. Moreover, the drug concentration in the hair of the pigmented rats was always much larger than that in the hair of the albino ones, although AUC and Cmax did not differ greatly between both rat groups. The findings suggest that ofloxacin is excreted in the hair in relation to the dose administered, and that the mechanism of the excretion is closely linked with the presence of melanin.

Animals↗
PubMed1992

Effects of antacids, ferrous sulfate, and ranitidine on absorption of DR-3355 in humans.

This study examined the effects of widely used antacids (aluminum hydroxide, magnesium oxide, and calcium carbonate), ferrous sulfate, and ranitidine on the absorption of a fluorinated quinolone, (-)-(S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro- 7H- pyrido-[1,2,3,-de][1,4]benzoxazine-6-carboxylic acid hemihydrate (DR-3355), in healthy male volunteers enrolled in three separate randomized crossover studies. Study 1 used 100-mg doses of DR-3355 and concurrent doses of aluminum hydroxide (1 g) or magnesium oxide (500 mg), while study 2 used DR-3355 (100 mg) and concurrent ferrous sulfate (160 mg) or calcium carbonate (1 g). Study 3 used DR-3355 (100 mg) and concurrent ranitidine (150 mg). Each study included control doses of DR-3355 (100 mg) alone. When aluminum hydroxide, ferrous sulfate, and magnesium oxide were coadministered with DR-3355, the relative bioavailability of DR-3355 was decreased to 56, 81, and 78%, respectively, of that for DR-3355 (100 mg) alone. Urinary excretion of DR-3355 was also significantly decreased by coadministration of these drugs. Thus, the magnitude of the decrease in the area under the concentration-time curve for DR-3355 varied among antacids, and the ranking of their inhibitory effects correlated with previously reported rankings of stability constants for chelate formation. DR-3355 bioavailability was not influenced by the concurrent administration of calcium carbonate and ranitidine, indicating that changes in gastric pH do not affect DR-3355 absorption.

Adult↗
PubMed1992

Species-related stereoselective disposition of ofloxacin in the rat, dog and monkey.

1. The stereoselective disposition of ofloxacin (OFLX) was studied in rats, dogs and monkeys after oral administration of racemic OFLX. 2. In rats serum concentrations of (R)-(+)-OFLX were much greater than those of (S)-(-)-OFLX, which is the active form of OFLX. In monkeys, by contrast, serum concentrations of (S)-(-)-OFLX predominated over (R)-(+)-OFLX levels. In dogs there were no differences in AUC or Cmax between the enantiomers. Thus, there exists a species-related difference in the stereoselective disposition of OFLX. 3. In rats the stereoselective differences were mainly due to stereoselective glucuronidation; OFLX is hardly metabolized in dogs, monkeys and humans. 4. In monkeys the AUC of (S)-(-)-OFLX was increased by co-administration of the (R)-(+)-form, indicating that the stereoselectivity of OFLX disposition in monkeys may be caused by competition between the enantiomers for renal excretion, especially for renal tubular secretion.

Administration, Oral↗
PubMed1991

High-performance liquid chromatographic determination of (S)-(-)-ofloxacin and its metabolites in serum and urine using a solid-phase clean-up.

A sensitive and selective method for the simultaneous determination of (S)-(-)-ofloxacin [(S)-(-)-OFLX] and its metabolites in serum and urine was developed using isocratic high-performance liquid chromatography with a specific solid-phase extraction procedure. (S)-(-)-OFLX and its metabolites, desmethyl-(S)-(-)-OFLX and (S)-(-)-OFLX N-oxide, were eluted from a C8 solid-phase column with recoveries of more than 98%. These compounds were separated and determined by means of a reversed-phase column with fluorimetric detection. Validation studies showed that the results were linear for (S)-(-)-OFLX in serum over the range 10-1200 ng/ml and in urine over the range 1-200 micrograms/ml. Analysis for (S)-(-)-OFLX and its metabolites showed good precision and accuracy with a relative standard deviation of less than 6%.

Chromatography, High Pressure Liquid↗
PubMed1991

Enantioselective disposition of ofloxacin in humans.

The enantioselective disposition of ofloxacin (OFLX) was studied in healthy subjects after oral administration of (+/-)-OFLX at a dose of 200 mg. S-(-)-OFLX and R-(+)-OFLX concentrations in serum and urine were measured separately by high-performance liquid chromatography, and various pharmacokinetic parameters were calculated from the data. The ratio of S-(-) to R-(+) enantiomer concentrations in serum showed a increase with time, with S/R ratios of 1.01 at 2 h and 1.31 at 24 h. The terminal elimination half-life of S-(-)-OFLX was 6.9 h, which was significantly greater (P less than 0.05) than that of the R-(+) enantiomer (6.3 h). S-(-)-OFLX also revealed a significantly greater area under the concentration-time curve in serum, mean residence time, and total body clearance than the R-(+) enantiomer did. The renal clearance of S-(-)-OFLX (7.14 liters/h/1.73 m2) was significantly lower than that of the R-(+) enantiomer (7.53 liters/h/1.73 m2). Although the difference in the pharmacokinetic parameters of the enantiomers was small, their disposition in humans was found to be stereoselective. The difference between the enantiomers may be explained by the difference in their renal excretion.

Administration, Oral↗
PubMed1991

[Intraocular penetration of DR-3355, a new quinolone derivative].

We studied the intraocular penetration of DR-3355, a new quinolone derivative in white mature rabbits. DR-3355 concentration in the aqueous humor reached the maximum, 1.06 micrograms/ml, at 2 hours after oral administration of 20 mg/kg in single dose. Six hours after it was 0.37 micrograms/ml. At 2 hours, the concentration ratio in the aqueous humor and serum was 23.3%. The pharmacokinetic parameters of DR-3355 levels in both of the aqueous humor and serum were: Cmax, 1.02 micrograms/ml and 4.56 micrograms/ml; Tmax, 1.42 hours and 1.47 hours; T 1/2, 0.96 hours and 1.57 hours; and AUC, 3.91 micrograms.hr/ml and 19.70 micrograms.hr/ml, respectively. At 2 hours after oral administration, the ocular tissue concentrations were 3.84-16.10 micrograms/g in the outer parts of the eye, and 0.70-13.52 micrograms/g or ml in the inner parts of the eye. Those concentrations decreased to about 1/2 to 1/32 in the outer parts, and 1/2 to 1/7 in the inner parts of the eye at 6 hours. Those ocular tissue concentrations of DR-3355 exceeded the MIC90 of the compound against various bacteria of ocular pathogens, such as Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae and Serratia marcescens.

Administration, Oral↗
PubMed1990

Modulation of Ca2+ transients and contractile properties by beta-adrenoceptor stimulation in ferret ventricular muscles.

1. The mechanism of modulation of Ca2+ transients and contraction by beta-adrenoceptor stimulation was studied in ferret ventricular muscles using aequorin to measure intracellular Ca2+. 2. Peaks of tension and light transients were increased by isoprenaline (10(-9) - 5 x 10(-7) M) which also abbreviated their time courses. 3. Time-to-peak tension was significantly shortened by 5 x 10(-9) M-isoprenaline and time-to-peak light was abbreviated by 10(-9) M-isoprenaline. 4. The time for the light to decay was shortened at 10(-9) M-isoprenaline. However, a higher concentration of isoprenaline (10(-8) M) was required for significant shortening of the half-relaxation time (TR50). 5. When isoprenaline was removed and beta-blocker (bupranolol, 1 microM) was applied, the time course of the light transients recovered but the time course of relaxation did not recover. 6. The relationship between [Ca2+]i and tension in tetanic contraction produced in the presence of ryanodine (5 microM) was shifted to the right by isoprenaline (10(-8) M). This was recovered by the replacement of isoprenaline with bupranolol (1 microM). 7. Isoprenaline (10(-7) M) added to the solution containing 20 mM [Ca2+]O and Bay K 8644 (1 microM), which produced maximal tension, caused a large light signal and enhancement of the initial phasic tension in tetanic contraction. However, the replacement of isoprenaline with bupranolol after immersing the preparation in 20 mM [Ca2+]O solution with Bay K 8644 and isoprenaline, did not significantly change the tension level, although the light signal decreased. Similar results were obtained in the ventricular muscle of young rats. 8. These results suggest that the dose dependence of modulation of the contractile element and sarcoplasmic reticulum (SR) by beta-adrenoceptor stimulation differs, and that additional factors, other than the faster Ca2+ uptake by SR and the decrease in Ca2+ sensitivity of the contractile element, might be involved in the shortening of the half-relaxation time by beta-adrenoceptor stimulation. In addition, beta-adrenoceptor stimulation does not produce a marked change in the maximal tension level.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Stereoselective metabolic disposition of enantiomers of ofloxacin in rats.

1. Stereoselective metabolic disposition of ofloxacin (OFLX) was studied in rats after oral administration of S-(-)-14C-OFLX and R-(+)-14C-OFLX at a dose of 20 mg/kg. 2. Radioactivity of the S-(-)-isomer was eliminated from blood much faster than that of the R-(+)-isomer. Marked differences in pharmacokinetic parameters exist between the enantiomers; the half life and AUC values of R-(+)-OFLX were greater than those of S-(-)-OFLX. Enantiomeric differences were also seen in the excretion of radioactivity, especially in biliary excretion. 3. 31.3 and 7.4% dose were excreted in the 8 h bile as ester glucuronides after oral administration of S-(-)- and R-(+)-OFLX, respectively. The enantiomeric difference in biliary excretion may be caused by stereoselective glucuronidation of S-(-)-OFLX to the ester glucuronide. 4. The metabolite pattern in serum and urine showed that the ester glucuronide of S-(-)-OFLX was more predominant than that of R-(+)-OFLX. 5. The stereoselective ester glucuronidation of the S-(-)-isomer in rats may induce significant differences in the pharmacokinetic parameters of S-(-)- and R-(+)-OFLX.

Animals↗
PubMed1988

Mechanism of action of 2, 3-butanedione 2-monoxime on contraction of frog skeletal muscle fibres.

The mechanism of the inhibitory effect of 2,3-butanedione 2-monoxime (BDM) on contraction of frog skeletal muscles was studied using skinned fibres and aequorin-injected intact fibres. The tension development of skinned fibres directly activated with calcium was strongly inhibited by BDM. This agent also had effects on the sarcoplasmic reticulum in the skinned preparations, suppressing the calcium pump function and enhancing the activity of the 'calcium-induced calcium release' mechanism. In electrically stimulated intact fibres, although BDM slightly suppressed the elevation of the intracellular calcium ion concentration, this effect was so weak that it would not explain the strong inhibitory effect of the agent on the tension development by the intact fibres. It was concluded that the tension reducing effect of BDM on intact fibres was due mainly to its direct action on the contractile system. The mode of this action of BDM was further examined with skinned fibres in view of its effects on the maximum shortening speed and isometric tension in low MgATP environments.

Animals↗
PubMed1988

Effect of new quinolones on drug-metabolizing enzyme system of rat hepatic microsomes.

Effects of repeated oral administration of new quinolones, ofloxacin, enoxacin and norfloxacin, once daily for 7 days, on the drug-metabolizing enzyme system of rat hepatic microsomes were studied in comparison with that of phenobarbital, a potent inducer of cytochromes P-450. Treatment of phenobarbital at the oral dose of 120 mg/kg induced significant increases in the contents of cytochrome P-450, cytochrome b5 and NADPH-cytochrome P-450 reductase and in the activity of ethoxycoumarin O-deethylase, and significant decreases in the activities of benzphetamine N-demethylase and aniline hydroxylase. However, ofloxacin, enoxacin and norfloxacin at the oral dose levels of 80 and 320 mg/kg showed no significant effect on the content of each constituent of the drug-metabolizing enzyme system, and the three enzyme activities. Thus, it is concluded that new quinolones including ofloxacin have no ability to induce a cytochrome-P-450-dependent monooxygenase system.

Animals↗
PubMed1988

Effects of exogenous ubidecarenone on cardiac action potential and activation time in hypoxic, glucose-free solution. Possible antiarrhythmic action of ubidecarenone.

Effects of ubidecarenone (coenzyme Q10, CoQ10, E-0216) on the cardiac action potential depressed by the superfusion with hypoxic, glucose-free solution (modified Tyrode solution) and on the activation time (ACT) altered by the same means were investigated. In the control specimens, the action potential duration (APD) was markedly shortened and action potential amplitude (AMP) reduced. The maximum rate of rise of phase zero Vmax) and the resting membrane potential (RMP) were slightly affected. Superfusion with exogenous CoQ10 significantly reversed the depressed APD and AMP, and tended to increase RMP and Vmax. Moreover, the ACT which, in the control, was slightly shortened until after the 10th min of superfusion became progressively longer. It was slightly prolonged during the first 10 min, and from the 12th to the 15th min was slightly shortened by treatment with CoQ10. These results suggest that CoQ10 could evoke an antiarrhythmic action in cardiac cells in depressed metabolic conditions.

Action Potentials↗
PubMed1987

Lack of effect of ofloxacin on theophylline pharmacokinetics in rats.

Effect of ofloxacin, a new quinolone antibacterial agent, on the pharmacokinetics of theophylline was studied in rats in comparison with that of enoxacin and cimetidine. Ofloxacin by pretreatment with five oral doses of 50 mg/kg did not increase serum concentrations of theophylline (5 mg/kg, i.v. single) and showed no significant effect on total body clearance, serum half-life (T1/2) and AUC of theophylline, while enoxacin by the same pretreatment increased significantly serum theophylline concentrations and resulted in significant effect on all the pharmacokinetic parameters. Coadministration of ofloxacin (80 mg/kg, p.o. twice) did not induce a significant effect on the pharmacokinetic parameters of theophylline at repeated doses (50 mg/kg, i.v., twice daily for 3 days). On the contrary, coadministration of enoxacin and cimetidine at the same dose as ofloxacin remarkably increased serum concentrations of theophylline at the same repeated doses, and caused a significant decrease in clearance and an increase in T1/2 and AUC. The three drugs had no influence on rat serum protein binding of theophylline. Ofloxacin exhibited a weak inhibitory effect on rat hepatic microsomal cytochrome P-450-dependent monooxygenases, whereas enoxacin and cimetidine induced a significant inhibition of the enzymes. Thus, it is concluded that ofloxacin has no significant effect on the pharmacokinetics of theophylline in rats, and that enoxacin raises serum theophylline concentrations and results in a significant effect on the theophylline pharmacokinetics by inhibition of the hepatic microsomal monooxygenases in rats.

Animals↗
PubMed1986

Isolation and identification of metabolites of ofloxacin in rats, dogs and monkeys.

Metabolites of (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid (ofloxacin) in excreta of rats, dogs and monkeys after oral administration of 14C-ofloxacin (20 mg/kg) were isolated and identified. Three metabolites of ofloxacin were detected in the excreta of all three species, and identified by t.l.c., u.v., n.m.r. and mass spectrometry as follows: M-1, ester glucuronide of ofloxacin; M-2, unchanged ofloxacin; M-3, (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid (desmethyl ofloxacin); M-4, (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid piperazine-4-oxide (ofloxacin N-oxide). It is concluded that ofloxacin is metabolized by O-acyl glucuronidation, N-demethylation and N-oxidation.

Animals↗