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H Hakusui

Publications and source records attributed to H Hakusui.

At least 37 records · Page 2Linked to original sources
PubMed1995

Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers.

The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluor o-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate, were investigated in healthy male Japanese volunteers after single (25, 50, 100, and 200 mg) and multiple (100 mg three times a day for 6 days plus once a day on the 7th day and 50 mg every 12 h for 13 doses) oral doses. DU-6859a was well tolerated at all doses, and all 36 subjects completed the study; mild transient soft stool in five volunteers and mild transient diarrhea in one volunteer on the multiple-dose (100 mg three times a day) study were the only side effects reported. No drug crystals were observed in the urine after the single 200-mg dose and the 100-mg three times a day regimen. DU-6859a was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 0.29 to 1.86 micrograms/ml for the 25- to 200-mg dose, and the mean time to reach Cmax ranged from 1.0 to 1.3 h. The terminal half-life ranged from 4.4 to 5.0 h. The area under the curve increased dose dependently. The serum protein binding of the drug was approximately 50%. The apparent volume of distribution clearly exceeded 1 liter/kg, suggesting good tissue penetration. Within 48 h, the cumulative urinary recovery of unchanged drug amounted to 69 to 74% of the dose administered, while fecal excretion up to 48 h after the 200-mg dose accounted for ca. 3% of the dose. Food intake did not affect the rate and extend of absorption of DU-6859a to a clinically significant extent. During multiple oral dosing, the accumulation of the drug in serum was close to the theoretically predicted values, which indicated that there was virtually no drug accumulation.

Administration, Oral↗
PubMed1995

Metabolism of irinotecan to SN-38 in a tissue-isolated tumor model.

The objective of this study is to investigate the metabolism of the antitumor drug, irinotecan (CPT-11), to its active metabolite, SN-38, in tumor tissue. Using Walker 256 carcinoma, we prepared a tissue-isolated tumor model: tumor preparation was continuously perfused with Krebs-Henseleit bicarbonate buffer containing 4% bovine serum albumin (BSA) and CPT-11 (10 micrograms/ml), and the concentration of SN-38 in the perfusate was monitored using HPLC. The concentration of SN-38 in the perfusate was gradually increased to a level of 9.69 ng/ml 60 min after the start of perfusion. As a control, an aliquot of the perfusate was separately incubated; however, no significant increase in SN-38 levels was observed. At the end of the perfusion, a part of the tumor tissue was homogenized and the level of SN-38 was determined; the levels in tumor tissue were 2.2-4.5 times higher than in the perfusate. From above results, CPT-11 was found to be metabolized to its active metabolite, SN-38, in tumor tissue--a desirable feature of an antitumor prodrug.

Animals↗
PubMed1995

Pharmacokinetics of SN-38 [(+)-(4S)-4,11-diethyl-4,9-dihydroxy-1H- pyrano[3',4':6,7]-indolizino[1,2-b]quinoline-3,14(4H,12H)-dione], an active metabolite of irinotecan, after a single intravenous dosing of 14C-SN-38 to rats.

Irinotecan (CPT-11) is a camptothecin derivative used for the treatment of cancer. It is a prodrug that is metabolized to its active form, SN-38 [(+)-(4S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]- indolizino[1,2-b]quinoline-3,14(4H,12H)-dione]. To clarify the pharmacokinetic difference between CPT-11 and SN-38, the plasma levels, tissue distribution and excretion of SN-38 were investigated after dosing rats with 14C-labeled SN-38. The plasma radioactivity showed bi-exponential decay with a terminal half-life of 9.91 h. TLC separation revealed that the plasma radioactivity consisted mainly of SN-38 at 5 min after dosing; however, it was soon replaced with SN-38 glucuronide (SN-38 Glu) and an unknown metabolite (M-2). The half-life of unchanged SN-38 after dosing with SN-38 was about 7 min, which was much shorter than that after dosing with CPT-11 (2.8 h) as reported previously. Its radioactivity was excreted mainly in feces (70.0% within 168 h), and biliary excretion (64.1% within 48 h) could account for the fecal excretion. The major component of urinary and biliary radioactivity was found by TLC to be SN-38. Whole body autoradiograms revealed that the tissue distribution of the radioactivity was low except in the liver and kidney. The radioactivity decreased rapidly and little was found in the body 24 h after dosing. In conclusion, SN-38 was excreted rapidly from bile and showed poor tissue distribution. These characteristics lead to a shorter SN-38 half-life, more so than dosing with CPT-11.

Animals↗
PubMed1995

Modulation of subcellular particles of the rat small intestine and liver by ebselen.

Reactions between ebselen and subcellular particles of rat liver were investigated by monitoring the activity of mitochondrial glutamate dehydrogenase and microsomal glucose 6-phosphate dehydrogenase. Rat small intestine lactate dehydrogenase was purified and was also used in the reaction between cytosolic protein and ebselen. Glutamate dehydrogenase in intact rat liver mitochondria was completely resistant to ebselen, but the enzyme was significantly inactivated in broken mitochondria mediated by Triton X-100, reflecting the fact that ebselen was not transported through the mitochondrial membrane into the matrix. Glucose 6-phosphate dehydrogenase in rat liver microsomes was inactivated by ebselen, accompanied by a slight decrease in the thiol groups of microsomal membrane protein. Purified cytosolic lactate dehydrogenase was inactivated concentration- and time-dependent by ebselen. The activity of rat small intestine lactate dehydrogenase abolished by ebselen was significantly restored by incubation with purified rat small intestine thioltransferase in the presence of reduced glutathione (GSH). The level of thiol groups in rat liver microsome membrane protein decreased by ebselen was partially restored by an incubation with purified rat liver thioltransferase in the presence of GSH. The results suggested that thioltransferase can cleave the Se-S conjugates between ebselen and cytosolic proteins or microsomal membrane proteins in the presence of GSH.

Animals↗
PubMed1995

Isolation and identification of seven metabolites of a water-soluble platelet aggregation inhibitor in rat urine.

1. Seven metabolites of 7-piperidino-1,2,3,4,5-tetrahydroimidazo[2,1- b]quinazolin-2-one dihydrochloride monohydrate (DN-9693) were isolated from rat urine by extraction with Amberlite XAD-2 and purification by silica gel and Sephadex LH-20 open-column chromatography and preparative high-performance liquid chromatography (hplc). The structure assignment of the metabolites was performed by field desorption mass spectrometry and 200-MHz Fourier transform nmr spectroscopic analysis and comparison with authentic standards when available. 2. DN-9693 underwent metabolism mainly at the piperidine ring to give the 4-hydroxypiperidine derivative (III) and 2-hydroxy-piperidine derivative, which is further metabolized to lactam (II) or delta-aminovaleric acid (V). The acyl side chain of V was shortened by beta-oxidation to form the 3-aminopropionic acid derivative (VII). V and/or VII underwent oxidative dealkylation to give the 7-amino derivative, which was conjugated with acetic acid to form the 7-acetylamino derivative (IV). DN-9693 also underwent hydrolysis of its lactam moiety to give VI. 3. The urinary excretion of III, V and VII was determined by liquid chromatography/electrochemistry (LC/EC) and V proved to be the major metabolite in rat urine. 4. A procedure is also presented for the identification of DN-9693 metabolites using LC/EC.

Animals↗
PubMed1995

Biliary metabolites of semotiadil fumarate in the rat.

After oral administration of 14C-semotiadil fumarate to rat, 81.3% of the dosed radioactivity was excreted into the bile. Five major biliary metabolites were detected and characterized as phenolic O-glucuronides by FAB mass spectrometry and 1H-nmr spectrometry. From these results it was concluded that the first step in the metabolism of semotiadil in rat was oxidations at various portions around the molecule to produce phenols. These oxidations implied the ring-opening of the methylenedioxy ring, O-demethylation of the methoxybenzene, hydroxylation of the ring, and aromatic N-demethylation. The next step was O-glucuronidation of the resulting intermediate phenolic metabolites.

Animals↗
PubMed1995

Pharmacokinetics and tolerance of a new fluoroquinolone antimicrobial drug after single oral doses in healthy volunteers.

1. The pharmacokinetics and tolerance of DV-7751a were investigated in healthy male Caucasian volunteers after single oral doses (100, 200, 400 and 800 mg). 2. DV-7751a was rapidly absorbed in the fasted state. The mean maximum concentration in plasma (Cmax) ranged from 0.27 to 1.98 micrograms/ml for the 100-800-mg dose and the mean time to reach Cmax (tmax) ranged from 1.1 to 1.9 h. The terminal half-life ranged from 8.75 to 10.0 h. A good linear correlation (r = 0.974) was found between doses from 100 to 800 mg and the resulting area under the concentration-time curve (AUC). The plasma protein binding of the drug was in the range of 57-65%. 3. Within 48 h, the cumulative urinary excretion of unchanged drug amounted to 22.0-26.8% of the dose administered. Faecal recovery of the drug up to 72 h after the 400-mg dose was about 12% of the dose given. 4. Adverse events thought to be possibly related to the drug included headache, rash, leg cramp, diarrhoea, abdominal pain, CNS depression and dizziness. DV-7751a, however, was well tolerated with no serious adverse events at any doses and all subjects completed the study. No drug crystals were observed in the urine.

Adult↗
PubMed1995

In vitro metabolism of nefiracetam by liver microsomes from rats, dogs and monkeys.

The in vitro metabolism of nefiracetam (CAS 77191-36-7, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, NEF, DM-9384), a novel cognition enhancer, has been investigated using liver microsomes from rats, dogs and monkeys. Microsomal metabolism of NEF showed qualitatively a similar profile in three species tested. Six metabolites were generated from incubation of NEF with liver microsomes. Their structures were identified using a thermospray LC/MS/MS (liquid chromatography/tandem mass spectrometry) method, as regioisomers of monhydroxylated derivatives of NEF: the 3-hydroxy (3-OH-NEF); 4-hydroxy (4-OH-NEF); 5-hydroxy (5-OH-NEF); 3'-hydroxy (3'-OH-NEF); 4'-hydroxy (4'-OH-NEF); hydroxymethyl (HM-NEF) metabolites. The heat lability, NADPH requirement and inhibition by prototype cytochrome P450 inhibitors (proadifen and metyrapone) implies that NEF oxidations are catalyzed by cytochromes P450. The major metabolic route was 5-OH-NEF formation in all species, corresponding well with the previous investigations in vivo. Inhibitory effects of alpha-naphthoflavone and quinidine on NEF hydroxylation suggest that several isoforms of cytochromes P450 are involved in the formation of these NEF metabolites.

Animals↗
PubMed1994

High-performance liquid chromatographic determination of the new quinolone antibacterial agent DU-6859a in human serum and urine using solid-phase extraction with photolysis-fluorescence detection.

A sensitive and specific HPLC method for the determination of DU-6859a (I), a fluoroquinolone antibacterial agent, in human serum and urine was developed. Compound I and the internal standard extracted from serum and urine by means of a Bond Elut C8 LRC cartridge showed recoveries of 96%. The extracts were chromatographed on a reversed-phase column with photolysis-fluorescence detection. This unique detection method was 42.5 times more sensitive than intrinsic fluorescence detection, the limits of detection being in 3.43 ng/ml for serum and 4.35 ng/ml for urine. In addition, I was stable in serum and urine for at least 1 month at -20 degrees C. The proposed method was sensitive and selective enough to apply to pharmacokinetic studies of I in humans after a single oral dose of 100 mg.

Anti-Infective Agents↗
PubMed1994

Radioimmunoassay for DS-4574, an antiallergic agent: development, evaluation, and application to human plasma samples.

A sensitive radioimmunoassay (RIA) method for DS-4574, an antiallergic drug, in plasma has been developed. As the three major metabolites have a hydroxyl group on the cyclohexyl ring, the triazole ring in the terminal part of molecule was attached to ovalbumin with a spacer of beta-chloropropionic acid succinimido ester to prepare an immunogen. Anti-DS-4574 antisera was obtained in rabbits immunized with the immunogen emulsified in Freund's complete adjuvant. The detection limit of the present RIA method was 1 mg/mL of plasma, which was 100-fold more sensitive than the HPLC method developed previously. Cross-reactivities with three major metabolites were less than 3%. The precision of the assay based on triplicate samples showed intra- and inter-assay coefficients of variations of less than 5% and 4%, respectively. This RIA method was applied to plasma samples of six volunteers who had received a single oral 10 mg dose of DS-4574. Plasma concentrations increased rapidly and reached 60 ng/mL at 0.5 h after administration. The concentration decreased to near the detection limit at 4 h postdose. The present RIA method was shown to possess adequate sensitivity to evaluate pharmacokinetic properties of the drug for clinical study, which was not possible by the HPLC method.

Adult↗
PubMed1994

Metabolic activation of CPT-11, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin, a novel antitumor agent, by carboxylesterase.

We measured the plasma concentrations of 7-ethyl-10-[4-(1-piperidino)-1- piperidine]carbonyloxycamptothecin (CPT-11) and the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), after treatment with CPT-11 to rats pretreated with bis-p-nitrophenylphosphate (BNPP) which is a specific inhibitor of carboxylesterase, and non-pretreated rats. The plasma level of SN-38 was decreased in the BNPP-pretreated group compared with these of non-pretreated group, indicating that the esterase involved in CPT-11 metabolism is a carboxylesterase. We also characterized the molecular species of carboxylesterase involved in CPT-11 metabolism using enzyme preparations purified from liver microsomes. Thirteen carboxylesterase isozyme activities towards CPT-11 were compared and guinea pig GLP1 was found to have the highest activity, while human HU1 isozyme had relatively lower activity than those of animal species. In studies on the kinetic parameters of the hydrolysis of CPT-11 by the purified carboxylesterase isozymes the highest Vmax value of the isozymes was found in human HU1 and the smallest was seen in rat RL1. The Vmax/Km for RL1 showed the largest value of 21.7 nmol/mg protein/mM.

Animals↗
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

Inhibitory activity of camptothecin derivatives against acetylcholinesterase in dogs and their binding activity to acetylcholine receptors in rats.

A camptothecin derivative, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), shows a potent antitumour activity in experimental tumour models and in clinical trials. However, CPT-11 induced early diarrhoea and vomiting at high dose levels in clinical studies and showed an acetylcholine-like action on the guinea-pig ileum and trachea. In the present study, we investigated the activities of camptothecin derivatives in inhibiting acetylcholinesterase (AChE) and in binding to muscarinic acetylcholine receptors (AChR). CPT-11 inhibited AChE and binding of the specific ligand to AChR with respective 50% inhibition concentrations of 0.2 and 5 microM. These inhibitions were induced by camptothecin derivatives having an amino group at the C-10 position (or the C-4 position of hexacyclic derivatives), but were not or were only slightly induced by the others. Early defecation and vomiting in dogs were observed after intravenous injection of DU-6596 and DU-6888, two hexacyclic derivatives having the aminomethyl group at the C-4 position, and of CPT-11. DU-6174, however, which has a hydroxy group at this position, induced no early defecation and little vomiting. Plasma concentrations of CPT-11, DU-6596 and DU-6888 after intravenous treatment at doses causing such early adverse effects were maintained for 1 h or longer at levels sufficient to inhibit AChE. These results suggest that the inhibition of AChE by camptothecin derivatives with an amino group at the C-10 position (or the C-4 position) relates to the early defecation or diarrhoea and vomiting.

Animals↗
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↗
PubMed1993

Pharmacokinetics of nefiracetam and three metabolites in humans and stereoselective hydroxylation of its pyrrolidine ring.

1. The kinetics of nefiracetam (I) and three metabolites (II-IV) were investigated in healthy volunteers. Compounds I-IV in serum and urine were measured by h.p.l.c. 2. After a single 200 mg dose of nefiracetam the drug was absorbed rapidly and showed peak serum levels of 16.3 +/- 0.9 nmol/ml. Cmax values of the three metabolites were comparatively low (0.96-4.89 nmol/ml), and tmax and t1/2 values of the metabolites (4.1-9.6 h and 7.8-21.9 h, respectively) were longer than those of I (1.6 h and 3.9 h respectively). Urinary excretion of I in 24 h was about 5% of the dose. The major urinary metabolite, a pyrrolidine ring scission product (IV), had a mean total excretion of 17.8% dose. The total of all four compounds in urine amounted to 43.4% dose. 3. In a multiple-dose study (daily 3 x 200 mg doses of nefiracetam for 7 days), the serum concentration profile of each compound indicated that the steady state was reached in 7 days. 4. Metabolite II existed as a racemate and III mainly as the (-)-enantiomer in human urine.

Adult↗
PubMed1992

Simultaneous determination of nefiracetam and its metabolites by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic assay was developed to simultaneously quantitate nefiracetam (NEF), a novel nootropic agent, and its three known oxidized metabolites (N-[(2,6-dimethylphenylcarbamoyl)methyl]succinamic acid (5-COOH-NEF), 4-hydroxy-NEF and 5-hydroxy-NEF) in human serum and urine. The quantitative procedure was based on solid-phase extraction with Sep-Pak C18 and ultraviolet detection at 210 nm. The calibration curves of NEF and the metabolites were linear over a wide range of concentrations (0.5-21.5 nmol/ml for NEF and 0.4-9.5 nmol/ml for metabolites in serum and 4-86 nmol/ml for NEF and 8-190 nmol/ml for metabolites in urine). Intra- and inter-day assay coefficients of variation for the compounds were less than 10%. The limit of detection was 0.1 nmol/ml for NEF, 5-COOH-NEF and 4-hydroxy-NEF, and 0.2 nmol/ml for 5-hydroxy-NEF in both serum and urine. This method is applicable for the determination of NEF and its metabolites in human serum and urine with satisfactory accuracy and precision.

Chromatography, High Pressure Liquid↗
PubMed1992

Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers.

The pharmacokinetic profile of nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide), a new nootropic agent, was studied in healthy Japanese male volunteers. Nefiracetam was administered orally at doses of 10-200 mg in the single-dose studies, and at doses of 200 mg three times a day for seven days in the multiple-dose study. An HPLC method was used to determine the concentrations of nefiracetam in serum, urine and faecal samples. Linear kinetic behaviour was obtained after single oral administration. Serum concentrations of nefiracetam reached maximum values (Cmax) within 2 h for all dosage groups, and declined monophasically after Cmax with half-lives of 3-5 h. The area under the concentration-time curve (AUC infinity) and Cmax were linearly related to the dose. The apparent clearance (CL) values were 94.4-140.3 mL min-1. Urinary excretion of nefiracetam was independent of the administered dose, and less than 10% of the dose was recovered in urine as the unchanged form within 24 h after administration. Renal clearance (CLR) did not change significantly as dose increased from 10 to 1200 mg. Faecal excretion of nefiracetam was less than 0.1% of the dose up to 24 h after a 300 mg oral dose. Food intake delayed the absorption of nefiracetam but did not significantly modify its pharmacokinetics. No clinically significant accumulation of nefiracetam in the body was observed during and after multiple doses.

Administration, Oral↗