Effect of timiperone on 3H-spiroperidol binding to rat striatal dopamine receptors.

The effects of timiperone, its metabolites and related compounds on specific 3H-spiroperidol binding to dopamine receptors in the rat corpus striatum were studied to clarify the affinity of timiperone, a new butyrophenone, for the receptors and whether timiperone itself was active in vivo. Timiperone had an approx. 0.6, 5 and 30 times greater affinity for the receptors than did spiroperidol, haloperidol and chlorpromazine, respectively. This affinity was observed specifically for antipsychotic drugs but not for diazepam and trihexyphenidyl. Timiperone metabolites had little or no affinity for the receptors. Radioreceptor assay values agreed well with the radiochemical assay for timiperone in the plasma and brain of rats after i.v. injection of the 14C-labeled drug. Thus, it is conceivable that timiperone itself exerts its potent antipsychotic activity by blockade of cerebral dopamine receptors.

Nonlinear pharmacokinetics of DQ-2556, a new 3-quaternary ammonium cephalosporin antibiotic, in rats caused by non-Michaelis-Menten type, dose-dependent renal clearance.

The pharmacokinetics and its dose dependency of a new cephalosporin, DQ-2556, were studied in the rat and rabbit. The pharmacokinetics of the compound in the rat was linear up to a dose of 300 mg/kg; however, at a dose of 1200 mg/kg, renal clearance decreased dramatically and the normalized area under the blood concentration-time curve increased remarkably. On the other hand, there were no dose-dependent changes in tissue/serum concentration ratios, serum protein binding, red cell binding, and the distribution of DQ-2556. In the rabbit, the pharmacokinetics of DQ-2556 was linear even up to a dose of 1200 mg/kg and no unusual pharmacokinetic behavior was observed. The renal clearance experiments demonstrated that DQ-2556 is excreted by glomerular filtration. It was also shown that the glomerular filtration rate (GFR) remained constant up to a dose of 1000 mg/kg of DQ-2556 in the rat, whereas the GFR decreased by 95.1% at a dose of 1200 mg/kg. The coincidence of dose relationship and species difference in the disorder of GFR and renal toxicity suggests that the change of pharmacokinetics of DQ-2556 was caused by its renal toxic effects at very high dose.

Effects of DM-9384, a pyrrolidone derivative, on ischemia-induced changes in the central monoamine systems.

Alterations in brain tissue levels of monoamines and monoamine metabolites were studied in gerbils 60 min after cerebral ischemia induced by 10 min carotid ligation after pretreatment with the antiischemic drug DM-9384 (1, 3, 10, 30 mg/kg, PO). The DA levels decreased in striatum after the ischemia, while cortical and hippocampal DA levels increased. The DOPAC levels increased in cortex, but were essentially unaffected in other regions. The HVA levels increased in all forebrain regions studied. NA levels decreased in hippocampus and superior colliculus, while a general increase in MHPG levels was seen. Decreases in 5-HT levels were seen in all forebrain regions except cortex. The 10 mg/kg and 30 mg/kg doses of DM-9384 counteracted the decrease in striatal 5-HT and hypothalamic MHPG/NA ratio, respectively. Thus pretreatment with DM-9384 exerted minor protective effects on the alterations induced in monoamine systems by transient forebrain ischemia.

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.

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.

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.

Determination of tranexamic acid in human serum by high-performance liquid chromatography using selective pre-column derivatization with phenyl isothiocyanate.

A high-performance liquid chromatographic method for determination of tranexamic acid in human serum using a selective derivatization has been developed. Tranexamic acid in the sample was allowed to react with phenyl isothiocyanate to form the phenylthiocarbamoyl derivative. Interfering alpha-amino acids in the sample were eliminated by selective derivatization to phenylthiohydantoin derivatives by acid treatment of the phenylthiocarbamoyl derivatives followed by solvent extraction. Then, the sample was analysed by conventional high-performance liquid chromatography with ultraviolet detection. The limit of detection of this method for serum sample was 0.2 micrograms/ml at a signal-to-noise ratio of 2. This method gave results comparable with those obtained by amino acid analysis (regression line: y = 0.4531x-0.02596, r = 0.9998, n = 21).

High-performance liquid chromatographic determination of a new nootropic, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, in human serum and urine.

A high-performance liquid chromatographic method for the determination of a novel nootropic agent, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (DM-9384, I), in human serum and urine has been developed. Compound I and the internal standard were extracted with chloroform from alkalinized serum and urine, and the organic layer was evaporated to dryness. The residue was chromatographed on a Nucleosil 7C18 reversed-phase column using 1/15 M potassium dihydrogen-phosphate-acetonitrile (7:3, v/v) as a mobile phase. Quantitation was achieved by monitoring the ultraviolet absorbance at 210 nm. The response was linear (0-2114.0 ng/ml) and the detection limits were 30 ng/ml for serum samples and 50 ng/ml for urine samples. The utility of the assay was demonstrated by determining compound I in serum and urine samples from three healthy male subjects receiving an oral dose of 30 mg of the drug. This method is satisfactorily sensitive and accurate, and is applicable for pharmacokinetic studies of I in humans.

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.

[Plasma levels of probucol in man after single and repeated oral doses (author's transl)]. / Taux plasmatiques du probucol chez l'homme après administration orale unique ou répétée.

Following administration of a single oral dose of 3 g probucol to healthy volunteers, mean peak plasma concentrations of 3.9 microgram/ml were observed at 24 hours. Successive blood levels measurements showed diphasic elimination, with half-lives of about 1 and 23 days. Plasma levels after a single 250 mg dose in volunteers are also reported. In 51 patients who received probucol 1 g daily for periods of 1 to 12 months, a concentration plateau was obtained within 1 to 3 months of treatment; the mean plasma levels ranged from 18.2 to 39.2 microgram/ml depending on the duration of probucol therapy. In another study carried out on 8 patients who were given the same daily dose during 12 months, the mean probucol plasma level at the end of that period was 18.9 microgram/ml. Repeated administration of probucol to healthy volunteers showed good correlation between dosage and blood levels.

Disposition of timiperone, 4'-fluoro-4-[4-(2-thioxo-1-benzimidazolinyl)piperidino]butyrophenone, a neuroleptic, in the rat on repeated oral dosage.

1. The metabolic disposition of [14C]timiperone was studied in male Wistar strain rats receiving an oral dose of 0.5 mg/kg consecutively daily for 21 days. 2. Blood concentrations of 14C indicate that absorption of [14C]timiperone on repeated dosage may be similar to that after a single dose. 3. Tissue levels of 14C after repeated doses were increased to up to double those after a single dose, but the decline of tissue concentrations after the 21st dose was similar to that after a single dose. Thus, no rat tissue show accumulation. 4. Repeated administration did not affect the metabolism of timiperone. 5. Excretion of 14C on the third day of repeated medication was urine, 44.7% and faeces 52.4% of the cumulative dose, and total daily excretions were more than approx. 97% of the cumulative dose in days 3-21 of the repeat dosage schedule.

Biotransformation of chlormezanone, 2-(4-chlorophenyl)-3-methyl-4-metathiazanone-1,1-dioxide, a muscle-relaxing and tranquillizing agent: the effect of combination with aspirin on its metabolic fate in rats and mice.

1. After oral administration of [14C]chlormezanone, about 74% of the dose was excreted into the urine of rats within 24 h and 21% into urine of mice within 2 h. 2. Biliary excretion of radioactivity was about 10% of the dose in rats. 3. Six metabolites in the urine of rats and mice were identified as p-chlorobenzoic acid, p-chlorohippuric acid, N-methyl-p-chlorobenzamide, 2-[N-methyl-N-(p-chlorobenzoyl)]carbamoylethylsulphonic acid, 3-sulphopropionic acid and the glucuronide of p-chlorobenzoid acid. 4. The effect of combination with aspirin on the metabolic fate of chlormezanone was investigated in rats and mice. Aspirin had no effect on the metabolite pattern in either species but reduced the rate of excretion, particularly in the mouse.

Simple method for determination of the cephalosporin DQ-2556 in biological fluids by high-performance liquid chromatography.

A sensitive method for the determination of DQ-2556 by high-performance liquid chromatography was established. The limits of detection for serum and urine were 0.1 and 2 micrograms/ml, respectively. Two clean-up procedures for serum samples were developed. In the first, deproteinization with 10% trichloroacetic acid was used and the recovery was 68.5%. In the other, ultrafiltration under acidic conditions was employed and the recovery was 85.1%. The former procedure is economical but complicated, whereas the latter is simple and labour-saving, but a special ultrafiltration tube is required. This situation offers a flexible choice, depending on the conditions of the laboratory.

Biotransformation of a new pyrrolidinone cognition-enhancing agent: isolation and identification of metabolites in human urine.

1. The metabolites of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (DMPPA; MH-1), in the urine of human volunteers have been investigated. 2. Ten metabolites together with the unchanged drug (MH-1) were isolated by h.p.l.c. and identified by n.m.r. and mass spectrometry as: three metabolites hydroxylated in the pyrrolidine ring of MH-1 (MH-2, MH-3 and MH-4), three metabolites hydroxylated in the dimethylphenyl ring of MH-1 (MH-6, MH-7 and MH-8), N-[(2,6-dimethylphenylcarbamoyl)methyl]-4-hydroxybutyrylamide++ + (MH-5), N-[(2,6-dimethylphenyl-carbamoyl)methyl]succinamic acid (MH-9), the 3-O-sulphate of MH-6 (MH-10) and the 3-O-sulphate of N-(2,6-dimethyl-3-hydroxyphenyl)-2-(5-hydroxy-2-oxo-1-pyrrolidinyl)aceta mide (MH-11). 3. DMPPA was extensively metabolized. The principal metabolic transformations were hydroxylation of the pyrrolidine ring at the C5 carbon followed by oxidative C-N cleavage, and hydroxylation of the phenyl ring followed by sulphate conjugation.

Metabolic disposition of DQ-2556, a new cephalosporin, in rats, rabbits, dogs, and monkeys.

The metabolic disposition of DQ-2556 was studied in rats, rabbits, dogs, and monkeys after an intravenous administration of 20 mg of 14C-labeled drug per kg of body weight. The serum data were analyzed by the two-compartment open model. The mean half-lives for the drug in serum at excretion phase were 18.1, 54.4, 21.8, and 63.6 min in rats, rabbits, dogs, and monkeys, respectively. The volume of distribution and total body clearance ranged from 0.18 to 0.30 liter/kg and 0.065 to 0.45 liter/h/kg, respectively. This compound was distributed to the tissues rapidly and well, especially to the kidney, trachea, liver, thyroid, skin, and lung. Tissue concentrations declined rapidly in a few hours and then very slowly. However, no accumulation was observed in any tissues. The results of a protein-binding study by ultracentrifugation indicated that DQ-2556 was 20 to 30% bound to serum proteins in animals and its affinity was low. Almost 90% of the administered radioactivity was excreted into urine in all species. Biliary excretion in rats was 3.1% of the dose. Nearly 70% of the dose or more was excreted into urine as unchanged drug, and the amounts of urinary metabolites were small except in rabbits, in which substantial amounts of polar metabolites were detected.