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Biomedical subjects

N Awata

Publications and source records attributed to N Awata.

At least 37 records · Page 2Linked to original sources
PubMed1994

Novel immunoaffinity extraction for liquid chromatographic determination of major metabolites of 4-acetoxy-2-(4-methylphenyl)benzothiazole in plasma.

Group extraction of the metabolites of 4-acetoxy-2-(4-methylphenyl)benzothiazole has been achieved through the use of an immunoaffinity adsorbent. The antisera elicited from an immunogen, 4-hydroxy-2-(4-formylphenyl)benzothiazole O-carboxymethyloxime-bovine serum albumin conjugate, were characterized to have a broad affinity spectrum for major metabolites oxidized at the 4-methyl group of the benzene moiety. One millilitre of the immunoaffinity adsorbent prepared by immobilization of antibodies (12.5 mg ml-1) was capable of retaining up to 4 micrograms of benzothiazoles. The adsorbates were recovered quantitatively by elution with 90% (v/v) methanol without any interfering peaks on the high-performance liquid chromatogram. The peak-height ratio of each metabolite to an internal standard was plotted against the concentration of the former substance; good linearity was observed in the range of 10-500 ng ml-1.

Animals↗
PubMed1994

Immunoaffinity extraction of 4-hydroxy-2-(4-methylphenyl)benzothiazole and its metabolites for determination by gas chromatography-mass spectrometry.

Immunoaffinity extraction of 4-hydroxy-2-(4-methylphenyl)benzothiazole and its metabolites, together with the corresponding meta-isomers has been achieved by the use of an antibody raised against an immunogen, an O-carboxymethyloxime-bovine serum albumin conjugate of 4-hydroxy-2-(4-formylphenyl)benzothiazole. The antibody produced exhibited a broad spectrum of affinity, not only for metabolites oxidized at the 4-methyl group of the benzene moiety but also for the corresponding meta-isomers. Up to 4 micrograms in total of these benzothiazoles could be extracted on the immunoaffinity adsorbent and recovered almost quantitatively by elution with 90% methanol. The resulting chromatogram was free from any interference. The eluted compounds were derivatized by conversion to their methyl esters and/or trimethylsilyl ethers, and subsequently separated into individual benzothiazoles by means of gas chromatography-mass spectrometry. The derivatized compounds were monitored using a characteristic ion, [M-CH3]+., and the limit of detection was 10 fmole. The peak height ratio of each metabolite to its corresponding meta-isomer internal standard was plotted against the concentration of the former and good linearity was observed over the range 0.2-5 ng/ml.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Enzyme immunoassay for 4-hydroxy-2-(4-methylphenyl)benzothiazole.

A specific enzyme immunoassay (EIA) has been developed for 4-hydroxy-2-(4-methylphenyl)benzothiazole (KB-2714) (1), an active metabolite of 4-acetoxy-2-(4-methylphenyl)benzothiazole (KB-2683) (2) which is a promising anti-rheumatic agent. The EIA was based upon antiserum elicited against 5-(2-carboxyphenylazo)-4-hydroxy-2-(4-methylphenyl)benzothiazole (3)-bovine serum albumin conjugate and beta-galactosidase-labelled 5-amino-4-hydroxy-2-(4-methylphenyl)benzothiazole (5). The sensitivity of the EIA was significantly improved by the utilization of a bridge heterologous combination system. An appropriate dose-response curve of EIA for 4-hydroxy-2-(4-methylphenyl)benzothiazole was obtained in the range of 10 pg tube-1-20 ng tube-1. The specificity of EIA proved to be satisfactory in terms of cross-reactivities to 14 benzothiazole-related compounds including glucuronic acid and sulphuric acid conjugates. The proposed method was evaluated to be useful for the determination of 1 in urine and plasma with acceptable recovery and inter- and intra-assay precision.

Antigens↗
PubMed1992

The biological fate of sodium prasterone sulfate after vaginal administration. I. Absorption and excretion in rats.

The absorption and excretion of sodium prasterone sulfate (PS) (sodium dehydroepiandrosterone sulfate) were studied in rats after vaginal administration of 14C-PS. In late pregnant rats, maximum plasma level (Cmax) appeared at 2-4 h after dosing and both Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally with increased dose up to 4.0 mg/kg. The radioactivity administered was almost completely recovered from urine and feces during a 72 h postdosing period. The percentages of radioactivity excreted in urine and feces were 58% and 40% of the dose, respectively. The biliary excretion was 46% of the dose within 48 h and about half of the radioactive biliary excreta entered the enterohepatic circulation system. The vaginal absorption of PS was markedly affected by the estrous cycle stage and the progress of pregnancy. The vaginal absorption of PS was predominant at metestrus and diestrus and during late pregnancy.

Absorption↗
PubMed1992

Contributions of various serum proteins to the binding of prasterone sulfate in humans.

The binding of prasterone sulfate (PS) in human plasma was investigated. Binding percentages of PS to human plasma, human serum albumin (HSA), human alpha 1-acid glycoprotein (AGP) and human gamma-globulin (GGL) were independent of the PS concentration between 0.1 and 8.0 micrograms/ml. The mean binding percentages were 99.1% for human plasma, 98.3% for HSA, 12.6% for AGP and 8.1% for GGL. Though PS is an acidic drug, binding of PS to AGP was observed. From the binding index, it was found that PS mainly bound to HSA in human plasma and that the contributions of AGP and GGL to PS in plasma were negligible.

Adult↗
PubMed1992

[Determination of the main metabolite (desethyl KBT-3022) of a new antiplatelet agent, KBT-3022 in plasma by gas chromatography].

A highly sensitive, accurate and reproducible gas chromatographic method for the determination of a main metabolite, 2-[4,5-bis(4-methoxy-phenyl)thiazol-2-yl] pyrrol-ylacetic acid (desethyl KBT-3022) of a new antiplatelet agent, ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate (KBT-3022), in the human or dog plasma has been developed. Desethyl KBT-3022 in the plasma was extracted with a mixture of n-hexane and dichloromethane (1:1), and was derivatized using pentafluorobenzyl bromide. The obtained pentafluorobenzyl derivative of desethyl KBT-3022 in the plasma was separated by high-performance liquid chromatography. After the separation, the pentafluorobenzyl derivative of desethyl KBT-3022 was detected by gas chromatography. Gas chromatography was performed with a Ultra 1 column (12 m x 0.22 mm i.d., film thickness 0.33 microns), using an electron capture detector. 2-[2-(4,5-Bis(4-methoxyphenyl)thiazol-2-yl)pyrrol-l-yl]propionic acid was used as an internal standard. The detection limit of desethyl KBT-3022 in the plasma was 0.2 ng/ml. The coefficients of variation were below 5.3%. This method was applied to the determination of the plasma concentration of desethyl KBT-3022 after oral administration of KBT-3022 to dogs.

Administration, Oral↗
PubMed1992

Usefulness of taurine in chronic congestive heart failure and its prospective application.

We compared the effect of oral administration of taurine (3 g/day) and coenzyme Q10 (CoQ10) (30 mg/day) in 17 patients with congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy, whose ejection fraction assessed by echocardiography was less than 50%. The changes in echocardiographic parameters produced by 6 weeks of treatment were evaluated in a double-blind fashion. In the taurine-treated group significant treatment effect was observed on systolic left ventricular function after 6 weeks. Such an effect was not observed in the CoQ10-treated group.

Administration, Oral↗
PubMed1991

Isolation and identification of the new metabolites of 1-[bis(4-fluorophenyl)-methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (KB-2796) from rat bile, urine and feces.

The metabolites of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (KB-2796) in the bile, urine and feces in rats were investigated after oral administration of [methine-14C], [benzyl-14C] and unlabelled KB-2796. Their structures were characterized by thin-layer chromatography, mass spectrometry, proton nuclear magnetic resonance and comparison with synthesized authentic compounds. The main pathways of biotransformation of KB-2796 in rats were: (a) O-demethylation at each methoxy group of the trimethoxybenzyl moiety, (b) N-dealkylation at 1 and 4-position of the piperazine ring and (c) hydroxylation at 5-position of the 2,3,4-trimethoxyphenyl ring.

Animals↗
PubMed1990

The effect of taurine on age-related immune decline in mice: the effect of taurine on T cell and B cell proliferative response under costimulation with ionomycin and phorbol myristate acetate.

Proliferative responses to the costimulation with phorbol-12-myristate-13-acetate (PMA) and suboptimal doses of ionomycin in the purified T and B cells from old mice were lower than those from young mice. The degree of the age-related decline was more significant in T cells than in B cells. Taurine, a sulfur containing amino acid, augmented the proliferative responses of T cells from both young and old mice. The augmentation of the proliferative response by taurine was more marked in old T cells than in young ones. The concentration of intracellular free calcium ion ([Ca2+]i) was significantly lower in the old T cells under the stimulation with PMA and ionomycin than that in the young ones. In the presence of taurine, the concentration of [Ca2+]i in the old T cell significantly increased under the stimulation. The results indicate that taurine improved the proliferative response of old T cells by the restoration of the increment of the concentration of [Ca2+]i under the stimulation.

Aging↗
PubMed1990

Determination of the antiplatelet agent. KB-3022, and its metabolite by high-performance liquid chromatography.

A rapid, accurate and reproducible high-performance liquid chromatographic method for the simultaneous determination of a new antiplatelet agent, ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate (KB-3022), and its main metabolite, 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetic acid (desethyl KB-3022), in biological fluids has been developed. KB-3022 and desethyl KB-3022 in plasma or urine were extracted with a mixture of n-hexane and dichloromethane (1:1), separated on a reversed-phase C18 column with a mixture of 0.01 M (NH4)2HPO4 (pH 3.0), acetonitrile and isopropyl alcohol as a mobile phase, and quantitated by ultraviolet absorbance measurement at 340 nm. 4-[2-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)pyrrol-1-yl]butyric acid was used as an internal standard. The detection limit of KB-3022 in plasma was 3 ng/ml, and that of KB-3022 in urine and desethyl KB-3022 in plasma or urine was 1 ng/ml. The coefficients of variation for the determination of KB-3022 or desethyl KB-3022 in plasma or urine were below 5.6%. This method was applied to the determination of the plasma concentration of KB-3022 and desethyl KB-3022 after intravenous administration to rats.

Animals↗
PubMed1990

Hepatic transport of an antiallergic agent, emedastine difumarate: interspecies difference in rats and guinea pigs.

Interspecies differences in the hepatic transport of an antiallergic agent, emedastine difumarate (KG-2413), were investigated in rats and guinea pigs, taking notice of the influx, efflux and metabolic processes. When the concentration of emedastine in the injection was varied from 2 microM to 10 mM, the extraction ratio of total radioactive compound to the liver at 18 s in rats and 25 s in guinea pigs after the rapid portal injection was more than 90% of the dose. This suggested that the influx velocity of emedastine into the liver was extremely fast, and that there was no interspecies difference in the influx process. The disappearance of unchanged emedastine from the liver was described by biexponential curve in rats and monoexponential curve in guinea pigs after rapid portal injection of 100 microM solution. This difference might be related to the interspecies difference in the binding of emedastine to the liver tissue. The time courses of disappearance of total radioactive compound and unchanged emedastine from the liver were analyzed using a compartment model for the examination of the efflux and metabolic processes. Emedastine was observed to have a pronounced interspecies difference in metabolic rate constant, but there was no pronounced interspecies difference in its efflux rate constant.

Animals↗
PubMed1990

[In vitro metabolism of an antiallergic agent, emedastine difumarate, in rats and guinea pigs].

In order to clarify the interspecies differences in the metabolism of emedastine difumarate (KG-2413), in vitro metabolism was studied with liver preparations of rats and guinea pigs. The activities of hydroxylase, N-oxidase and N-demethylase, of emedastine were evaluated with liver 9000 x g supernatant and microsomes. As the results, the orders of activities were as follows; 5-hydroxylase greater than or equal to N-oxidase greater than 6-hydroxylase greater than N-demethylase in rats, and N-oxidase much greater than N-demethylase greater than 6-hydroxylase greater than 5-hydroxylase in guinea pigs. Emedastine N-oxide, little excreted into the urine of rats, was largely formed in vitro, so it was assumed that N-oxide reduction was important in vivo. The reductase activity of emedastine N-oxide was evaluated, and compared with N-oxidase activity of emedastine. In rats, the reductase activity was nearly equal to the N-oxidase activity, and relatively high even under aerobic conditions. On the other hand, in guinea pigs, the reductase activity was lower than the N-oxidase activity. It was considered that relative activities of the N-oxidation of tertiary amine in a 1,4-diazepine ring of emedastine and the reduction of N-oxide once formed were one of the factors of interspecies differences of metabolism of emedastine in rats and guinea pigs.

Animals↗
PubMed1989

Pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1, 4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413) after oral administration: interspecies differences in rats, guinea pigs and dogs.

The pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1, 4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413) after oral administration were studied in rats, guinea pigs and dogs. Maximum plasma level (Cmax) appeared at 23, 32 and 51 min after dosing in rats, guinea pigs and dogs, respectively. Plasma half-lives of the terminal phase were comparable to those after intravenous administration in each animal species. Pronounced interspecies differences were observed in the Cmax/dose and area under the plasma concentration-time curve (AUC)/dose, namely, these values were high in guinea pigs and low in rats and dogs. The extents of bioavailability were 0.036 in rats (20 mg/kg), 0.50 in guinea pigs (2 mg/kg) and 0.052 in dogs (2 mg/kg). These variations in the pharmacokinetic parameters in the animals were assumed to be mostly due to the species difference in the hepatic intrinsic clearance.

Administration, Oral↗
PubMed1989

The effect of bile salts on the oral mucosal absorption of human calcitonin in rats.

The relationship between the inhibition of the degradation of human calcitonin (HCT) in the supernatant of the rat's oral mucosa homogenate and the promoting effect on the rat's oral mucosal absorption of HCT was investigated by using ten kinds of sodium bile salts. The promoting effects and the inhibition of the degradation by the dihydroxy bile salts were related to the hydrophobicity, respectively. The inhibition of the degradation of HCT was related to the promoting effect on the oral mucosal absorption of HCT in the presence of the dihydroxy bile salts and to the concentration of the bile salts. Furthermore, the micelle formed by the bile salts would be concerned with the inhibition of the degradation of HCT.

Absorption↗
PubMed1989

Interspecies differences in pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl) benzimidazole difumarate (KG-2413) after intravenous administration to rats, guinea pigs and dogs.

Interspecies differences in the pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimid azole difumarate (KG-2413) after intravenous administration were investigated in rats, guinea pigs and dogs. The disappearance of unchanged KG-2413 base was described by biexponential curves in all three animal species. The areas under the plasma concentration-time curves (AUC) in rats, guinea pigs and dogs were 218, 421 and 369 ng.h/ml, respectively, at a dose of 2 mg/kg. The volume of distribution in rats was comparable to that in dogs, and was about three times greater than that in guinea pigs. This might be due to the difference in the unbound fractions of KG-2413 base in plasma (fu), that is, the values of fu in rats, dogs and guinea pigs were 0.607, 0.603 and 0.189, respectively. The first-order elimination rate constant from the central compartment (kcl) in dogs were smaller than those in rats and guinea pigs. Total body clearances (CLtot) of KG-2413 base in rats and guinea pigs were comparable to the hepatic blood flow rate (Q) of each animal. Assuming that KG-2413 base is only eliminated in the liver, relatively rapid metabolism of KG-2413 base occurred in the liver of rats and guinea pigs. In dogs, extrahepatic elimination was suggested because the value of CLtot seemed to be greater than that of Q.

Animals↗
PubMed1989

[Selective and sensitive determination of an antiallergic agent, emedastine difumarate (KG-2413), in human plasma by the radioreceptor assay combined with a high-performance liquid chromatography].

The selective and sensitive method for the determination of a new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-b enzimidazole difumarate (emedastine difumarate, KG-2413), in the human plasma has been developed. Emedastine was determined by the receptor assay after the separation from its metabolites by the use of high-performance liquid chromatography (HPLC). This combined method (HPLC-radioreceptor assay (RRA) method) allowed us the quantification only of 0.3 ng/ml of emedastine in the human plasma. The intra-assay coefficients of variation for the determination were below 12%. Furthermore, the total pharmacologically active metabolites, including unchanged emedastine, was determined by the extraction of the unconjugated metabolites in the human plasma with chloroform followed by the receptor assay (RRA method). The human plasma concentrations measured by the HPLC-RRA method were in good agreement with those by the RRA method. These results suggested that in human pharmacological activities occurred by unchanged emedastine itself.

Adult↗
PubMed1989

[Identification of the metabolites of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepine-1-yl)-1H- benzimidazole difumarate (KG-2413), in rats].

The urinary and biliary metabolites of a new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepine-1-yl)-1H-b enzimidazole difumarate (KG-2413) in rats were identified by using a 14C-labelled drug and instrumental analyses, e.g., high performance liquid chromatography, gas chromatography (GC), 1H nuclear magnetic resonance, mass spectrometry (MS) and GC/MS. A slight amount of KG-2413 free base was detected only in the unconjugated fraction of urine. The main pathways of biotransformation of KG-2413 in rats were: (a) aromatic hydroxylation in the benzimidazole ring, (b) N-oxidation and N-demethylation in the 1,4-diazepine ring, (c) alpha-carbon oxidation (lactam formation) in the 1,4-diazepine ring (d) O-deethylation in the N-ethoxyethyl side chain. Regioselectivity was observed for aromatic hydroxylation, as only two of the four possible monohydroxylated metabolites could be detected. Furthermore, N-oxidation and lactam formation reactions were found to be regiospecific, that is, the former took place only at the position of 4-N atom and the latter at 5-C atom, respectively.

Animals↗