Biomedical subjects

Shuichi Takeda

Publications and source records attributed to Shuichi Takeda.

36 records · Page 2Linked to original sources

PubMed2005

Antianginal effects of lercanidipine on the vasopressin or methacholine induced anginal model in rats.

The antianginal effects of lercanidipine, a newly synthesized 1,4-dihydropyridine derivative calcium channel antagonist, were evaluated in experimental angina model rats and the effects were compared with those of nifedipine, benidipine and amlodipine. In the vasopressin-induced angina model, intravenous administration of lercanidipine dose-dependently suppressed vasopressin-induced ST-depression. Amlodipine barely suppressed it, while benidipine, at the same dose, completely suppressed it. Nifedipine had a potency between that of amlodipine and benidipine. Oral administration of lercanidipine showed similar effects to the intravenous administration test on ST change. High doses of amlodipine, benidipine and nifedipine suppressed ST-depression by almost 100%. In the methacholine-induced angina model, lercanidipine suppressed the ST elevation dose dependently. Amlodipine barely suppressed it, while benidipine at 30 microg/kg effected almost total suppression. Nifedipine had a potency between that of amlodipine and benidipine. Intraduodenal administration of lercanidipine also suppressed the ST-elevation dose dependently. Nifedipine, benidipine and amlodipine at 10 mg/kg all markedly suppressed the elevation. Lercanidipine was more potent than the other calcium channel antagonists tested. In conclusion, it was explicitly demonstrated that lercanidipine exerts potent protective effects on the ischemic electrocardiography (ECG) changes in a variety of putative angina pectoris models in rats. An antispasmolytic coronary vasodilating action may be involved in the mechanism. It is expected that lercanidipine will be useful as an antianginal agent.

Angina Pectoris↗

PubMed2005

Synthesis of a capillarisin sulfur-analogue possessing aldose reductase inhibitory activity by selective isopropylation.

We describe the synthesis of 2-[(4-hydroxyphenyl)thio]-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 2 from 3,4,5-trimethoxyphenol 6 via the key intermediate, 3-iodo-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one 3. An important feature of this synthetic scheme involves selective alkylation, which can be achieved by two different routes. One route involves the selective isopropylation of a triacetate derivative 4 under basic conditions. The second route employs the selective demethylation of a trimethoxy derivative 5 under acidic conditions followed by isopropylation. The product of these alternative routes, compound 3, is then converted to a capillarisin sulfur analogue 2 in a one-pot reaction via the imidazolyl intermediate 22.

Aldehyde Reductase↗

PubMed2005

A new acetylenic compound from the rhizomes of Atractylodes chinensis and its absolute configuration.

A new acetylenic compound "atractyloyne", (3S,4E,6E,12E)-1-isovaleryloxy-tetradeca-4,6,12-triene-8,10-diyne-3,14-diol (1) was isolated from the rhizomes of Atractylodes chinensis (Compositae) together with a known compound (4E,6E,12E)-3-isovaleryloxy-tetradeca-4,6,12-triene-8,10-diyne-1,14-diol (2). These structures were determined on the basis of the spectroscopic data and chemical evidence, and the absolute configuration of 1 was established by the modified 2-methoxy-2-trifluoromethylphenylacetic acid (MTPA) method.

Acetylene↗

PubMed2005

Diabetic complications in a new animal model (TSOD mouse) of spontaneous NIDDM with obesity.

The TSOD mouse has been established as an inbred strain with spontaneous development of diabetes mellitus as the first clinical signs of diabetes. Polydipsia and polyuria are observed at about 2 months old only in male mice, after which hyperglycemia and hyperinsulinemia are detected. Following these symptoms obesity gradually develops until about 12 months old. In histopathological examination of the pancreas, severe hypertrophy of pancreatic islets was observed due to proliferation and swelling of B cells. In the kidney, thickening of the basement membrane in glomeruli and an increase of the mesangial area were observed at 18 months old. Motor neuropathy in TSOD mice began to appear at 14 months old and most male mice at 17 months old showed weakness of front and hind paws caused by neuron degeneration in the peripheral nerve. In sensory neuropathy, the threshold in the tail pressure test decreased significantly at 12 months old. Light microscopic and electron microscopic examination of sciatic nerves showed a decrease in the density of nerve fibers by the endoneural fibrosis and loss of these fibers. Degenerative changes of myelinated fibers, separation of myelin sheaths with intralamellar edema and remyelination were frequently observed. In the severely affected nerve fibers, the lamellar structure was completely destroyed and macrophages migrated around the myelin sheath or invaded the intramyelin space. Considering these findings similar to non-insulin dependent diabetes mellitus (NIDDM) in humans, the TSOD mouse should be a useful model for the pathogenic study of diabetic complications, especially of peripheral neuropathy.

Animals↗

PubMed2004

Separation and isolation methods for analysis of the active principles of Sho-saiko-to (SST) oriental medicine.

Sho-saiko-to (SST) was introduced into Japan as an oriental classical medicine from China approximately 1500 years ago, and it is currently the most representative Kampo medicine (traditional Japanese medicine). SST is manufactured in Japan as an ethical drug on a modern industrial scale in which the quality of ingredients is standardized with Good Manufacturing Practices (GMP) regulation. SST is widely used for the treatment of chronic hepatitis. Experimental and clinical studies including multi-center, placebo-controlled, double-blind studies have demonstrated the various pharmacological effects of SST. SST is prepared from the hot water extraction of seven raw materials, therefore many kinds of constituents are included. Three-dimensional (3D) HPLC analysis is useful for obtaining many kinds of constituents, especially low molecular ultraviolet (UV) quenching compounds, contained in SST as well as its fractions. Fingerprint pattern provided by 3D HPLC analysis makes possible to identify the overall-viewing of SST. Databases of UV spectra of the components of medicinal herbs obtained by reversed-phase (RP) HPLC using a photodiode array (PDA) and fingerprint patterns of crude drugs made by 3D HPLC analysis facilitate the identification, analysis and quality of herbal drugs. Studies using both PDA HPLC and an amino acid analysis with a fluorometric detector have found that SST contains fifteen major low molecular compounds (i.e. baicalin, wogonin-7-O-glucuronide, liquiritin, their three aglycons, liquiritin apioside, glycyrrhizin, saikosaponin b1, saikosaponin b2, ginsenoside Rg1, ginsenoside Rb1, (6)-gingerol, (6)-shogaol and arginine). These compounds have various pharmacological actions, and are assumed to be responsible, at least partly, for the pharmacological effects of SST. Although there have only been a few investigations on high molecular compounds with pharmacological actions contained in SST, several kinds of polysaccharides have been isolated from constituent herbs of SST. This review paper summarizes analytical methods of separation, isolation and identification of compounds with biological activities from SST, which is a mixture drug of medicinal herbs. Accordingly, this paper would not focus on methods of separation, isolation and analysis of particular compounds from each constituent herb of SST.

Chromatography, High Pressure Liquid↗

PubMed2004

Endogenous glucocorticoids are essential for maintaining prefrontal cortical cognitive function.

Glucocorticoid hormones are important in the maintenance of many brain functions. Although their receptors are distributed abundantly throughout the brain, including the prefrontal cortex (PFC), it is not clear how glucocorticoid functions, particularly with regard to cognitive processing in the PFC. There is evidence of PFC cognitive deficits such as working memory impairment in several stress-related neuropsychiatric disorders, including depression, schizophrenia, and Parkinson's disease. Disruption of the hypothalamo-pituitary-adrenal (HPA) system, which is characterized by attenuated glucocorticoid negative feedback, is also observed. In rats, chronic stress induces working memory impairment as a result of decreased dopaminergic transmission in the PFC. These chronically stressed rats also show HPA disruption; this is caused in part by a reduced glucocorticoid response in the PFC. These findings implicate reduced glucocorticoid actions in working memory impairment. In the present study, we examined the effects of the suppression of endogenous glucocorticoids by adrenalectomy (ADX) on working memory in rats and explored the involvement of PFC dopaminergic activities in memory. The ADX impaired working memory, decreased dopamine release, and upregulated D1 receptors in the PFC. These dysfunctions were prevented by corticosterone replacement that reproduced normal physiological plasma levels, indicating that suppression of glucocorticoids causes these dysfunctions. Moreover, the ADX-induced working memory impairment was ameliorated by intra-PFC infusions of a D1 receptor agonist, SKF 81297. Thus, suppression of glucocorticoids impaired working memory through a D1 receptor-mediated hypodopaminergic mechanism in the PFC. This finding indicates that endogenous glucocorticoids are essential for maintaining PFC cognitive function and suggests that HPA disruption contributes to PFC cognitive deficits.

Adrenalectomy↗

PubMed2004

Effects of the traditional Japanese medicine Unkei-to on the corticotropin-releasing factor-induced increase in locomotor activity.

The effect of Unkei-to, a traditional Japanese herbal medicine and strong in vitro releaser of cytokine-induced neutrophil chemoattractant (CINC), on the increase in locomotor activity induced by intracerebroventricular (icv) injection of corticotropin-releasing factor (CRF) in male rats in a familiar environment was investigated. Oral administration of Unkei-to (100 mg/kg) for 1 week significantly attenuated the CRF-induced increase in locomotor activity. Unkei-to also reduced the CRF-induced accumulation of hypothalamic CINC, which has a functional antagonistic action on the response to CRF; the reduction may reflect an increased release of CINC. These results suggest that Unkei-to has an alleviative effect on the action induced by brain CRF and the mechanism of this effect may partly involve CINC.

Animals↗

PubMed2004

Prevention by 17beta-estradiol and progesterone of calcitonin gene-related peptide-induced elevation of skin temperature in castrated male rats.

OBJECTIVES: To clarify the relationship between calcitonin gene-related peptide (CGRP) and ovarian hormones (17beta-estradiol and progesterone) in hot flashes in men who undergo androgen deprivation therapy for prostate cancer, we studied the effects of ovarian hormones on CGRP-induced elevation of skin temperature in castrated male rats. The results were compared with those from rats treated with testosterone replacement. METHODS: Adult male rats were castrated by either a single injection of gonadotropin-releasing hormone analogue (Leuplin, 1.0 mg/kg, subcutaneously) or bilateral orchiectomy. The castrated animals were subcutaneously injected daily for 14 days with ovarian hormones, testosterone, or olive oil as the vehicle. On the day after the final administration of the drug, the changes in skin temperature induced by exogenous CGRP (10 mug/kg intravenously), serum testosterone concentration, and prostate weight were measured. RESULTS: The CGRP-induced elevation of skin temperature was significantly greater in the castrated rats than in the sham-treated rats. This potentiation was significantly inhibited by treatment with ovarian hormones, as well as by testosterone replacement. The testosterone replacement restored decreases in both the serum testosterone level and the prostate weight due to castration; the treatment with ovarian hormones did not affect them. CONCLUSIONS: 17beta-Estradiol and progesterone, which do not confer testosterone activity on serum, may be useful for the treatment of hot flashes in patients for whom testosterone replacement therapy is contraindicated, such as those with prostate carcinoma. In addition, we suggest that CGRP is closely involved in the amelioration of hot flashes by ovarian hormones in men who undergo androgen deprivation therapy.

Animals↗

PubMed2004

The diuretic effect of Sairei-to is mediated by nitric oxide production in pentobarbital-anesthetized rats.

Sairei-to (TJ-114), a Japanese traditional medicine, has been used clinically for the treatment of various edematous disorders. The inhibitory effect on edema may be dependent on the diuretic response to TJ-114. This study was conducted to clarify the mechanism of diuresis. Pentobarbital-anesthetized rats were infused with a saline solution intravenously (0.4 mL/30 min). Urine was collected through a bladder cannula for 30 min. Intraduodenal administration of TJ-114 (0.5 - 1.5 g/kg) resulted in a dose-dependent increase of urine volume with insignificant urinary sodium excretion and significant urea excretion, but no effect on mean arterial blood pressure. Furthermore, TJ-114 significantly increased urinary levels of NO(2) + NO(3). In addition, intraperitoneal pre-treatment with 6 mg/kg of N(G)-nitro-L-arginine methyl ester inhibited the increase in urine volume, urinary urea excretion, and urinary levels of NO(2) + NO(3) in the rats treated with TJ-114. These results suggest that TJ-114 induces a diuretic response via production of NO.

Adjuvants, Anesthesia↗

PubMed2003

Permeability of the flavonoids liquiritigenin and its glycosides in licorice roots and davidigenin, a hydrogenated metabolite of liquiritigenin, using human intestinal cell line Caco-2.

The present investigation focused on the transepithelial flux of liquiritigenin (LG), davidigenin (DG), liquiritin (LQ), and liquiritin apioside (LA) using the human colonic cell line Caco-2 as a model of human intestinal absorption. Apparent permeability coefficients (Papp) for the apical to basolateral flux of LG and DG were (16.0 +/- 0.727) x 10(-6) cm/s and (18.2 +/- 1.67) x 10(-6) cm/s, respectively. These Papp were higher than that of the transcellular transport marker propranolol (13.5 +/- 0.34) x 10(-6) cm/s (P < 0.01). Papp for the apical to basolateral flux of LQ and LA were (0.26 +/- 0.12) x 10(-6) cm/s and (0.075 +/- 0.005) x 10(-6) cm/s, respectively. These Papp were lower than that of the paracellular transport marker mannitol (0.64 +/- 0.04) x 10(-6) cm/s (LG, P < 0.01; LA, P < 0.001). These data suggested excellent absorption of LG and DG through the human intestinal epithelial cell line. On the contrary, poor absorption of LQ and LA was expected due to the little transepithelial flux of these compounds in the human colonic cell line Caco-2.

Caco-2 Cells↗

PubMed2003

Involvement of calcitonin gene-related peptide in elevation of skin temperature in castrated male rats.

OBJECTIVES: To assess the involvement of calcitonin gene-related peptide (CGRP) in the occurrence of hot flashes in men after castration for treatment of prostate cancer, we investigated the effects of CGRP on skin temperature in surgically and medically castrated male rats. METHODS: Changes in skin temperature of the hind paws after intravenous injection of 10 microg/kg of CGRP and CGRP family peptides (adrenomedullin and amylin) were measured at 5-minute intervals for 120 minutes, 3 weeks after bilateral orchiectomy or 2 weeks after subcutaneous injection of a gonadotropin-releasing hormone analogue (1.0 mg/kg Leuplin) in male rats. Antagonism with CGRP8-37 (1000 microg/kg intravenously), a CGRP1 receptor antagonist, to the CGRP-induced response was examined by injecting it 10 minutes before injection of CGRP. The effect of testosterone replacement on castration was evaluated in each castrated rat by the administration of testosterone (1.0 mg/kg subcutaneously once a day) for 14 days before the day of the temperature analysis. RESULTS: CGRP, but not adrenomedullin and amylin, elevated the skin temperature in surgical or medical castration-induced testosterone-deficient rats more than in the sham-treated rats. The difference was statistically significant. The CGRP-induced potentiation in the castrated rats was inhibited by pretreating with CGRP8-37 or by supplying testosterone. CONCLUSIONS: CGRP is the most potent peptide in a family that elevates the skin temperature in male rats. The elevation of the skin temperature was more affected by the testosterone deficiency resulting from castration. These results suggest that CGRP is involved in the mechanism underlying hot flashes in men.

Adrenomedullin↗

PubMed2003

Significance of measured elevation of skin temperature induced by calcitonin gene-related peptide in anaesthetized rats.

To assess whether peripheral changes related to skin temperature rise were induced by ovarian hormone deficiency, we investigated the effects of anaesthesia on calcitonin gene-related peptide (CGRP)- or luteinizing hormone-releasing hormone (LH-RH)-induced elevation of skin temperature in female rats. CGRP was used as an inducer of peripherally-mediated elevation of skin temperature, whereas LH-RH was used as an inducer of centrally-mediated elevation of skin temperature. Intravenous (i.v.) but not intracerebroventricular injection of CGRP (10 microg kg(-1)) or intracerebroventricular but not intravenous injection of LH-RH (10 microg/rat) elevated the skin temperature of unanaesthetized rats restrained in a Ballman's cage. The elevation with LH-RH was completely inhibited by urethane anaesthesia, whereas the elevation with CGRP was not. These results suggested that changes in skin temperature measured under anaesthesia reflected a peripherally rather than a centrally mediated mechanism. The CGRP (1.0-30 microg kg(-1), i.v.)-induced elevation of skin temperature was potentiated in ovariectomized rats and inhibited by pretreatment with a CGRP receptor antagonist CGRP(8-37) (1000 microg kg(-1), i.v.), suggesting that the potentiation may participate in peripheral factors such as a postsynaptic hypersensitivity to CGRP following ovarian hormone deficiency. Thus, measurement of skin temperature in the anaesthetized rat was a useful procedure to seek the peripheral mechanism of potentiation of skin temperature induced by CGRP, thought to be closely related to menopausal hot flashes.

Adjuvants, Anesthesia↗

PubMed2003

Pharmacokinetics of (-)-epicatechin-3-O-gallate, an active component of Onpi-to, in rats.

(-)-Epicatechin-3-O-gallate (ECG), a component of Rhei Rhizoma, is one of the active components of Onpi-to, a herbal medicine composed of five crude drugs (Rhei Rhizome, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), which has been used in patients with chronic renal failure. Pharmacokinetics of ECG was investigated in male rats employing an HPLC-electrochemical detection method. 1. Following oral administration of ECG, ECG plasma levels revealed curves characterized by peaks at 0.065, 0.063 and 0.085 h corresponding to dosages of 12.5, 25.0 and 50.0 mg/kg at mean concentrations of 49.62, 212.89 and 464.04 ng/ml, respectively. Plasma levels subsequently declined bi-exponentially. ECG demonstrated nonlinear pharmacokinetics in terms of C(max) and AUC(0-inf). 2. The absolute bioavailability values (F) were 1.02, 1.47 and 3.30% at doses of 12.5, 25.0, and 50.0 mg/kg, respectively. 3. Following intravenous injection of ECG, plasma levels of ECG decreased with the gamma-elimination half-life (t(1/2gamma)) of 4.03 h. 4. Following oral administration of ECG, urinary levels of ECG were lower than the quantitation limit. Moreover, cumulative excretion of the metabolites, delta-(3,4-dihydroxyphenyl)-gamma-valerolactone and delta-(3-methoxy-4-hydroxyphenyl)-gamma-valerolactone, was 2.45 and 0.23% of dose, respectively, up to 30 h after dosing.

Administration, Oral↗

PubMed2003

Pharmacokinetics of rhein from Onpi-to, an Oriental herbal medicine, in rats.

Onpi-to, an herbal medicine composed of five crude drugs (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), was administered orally to rats. Onpi-to includes 1.240% of total potential rhein derived from sennoside A, sennoside B, rhein 8-O-glucopyranoside and rhein. Plasma, urinary and biliary levels of rhein were determined by an HPLC-UV method. The plasma levels displayed curves characterized by maximum peaks at 8.3+/-5.2 min, 8.3+/-5.2 min and 20.0+/-21.9 min following dosages of 125, 250 and 500 mg/kg with mean concentrations of 1302.5+/-926.4, 2973.6+/-684.3 and 3118.8+/-1701.2 ng/ml, respectively, followed by a subsequent decline. Area under the concentration-time curve (AUC)(0-48 h) at doses of 125, 250 and 500 mg/kg were 752.3+/-321.5, 2443.3+/-554.4 and 4443.2+/-2641.3 ng.h/ml, respectively. In female rats, rhein plasma levels showed curves which had a maximum peak at 45.0+/-16.4 min after a dosage of 250 mg/kg with mean concentration of 3058.0+/-1533.7 ng/ml, followed by a subsequent decline. AUC(0-48 h) was 5537.7+/-1876.0 ng.h/ml. The cumulative urinary excretion of rhein and of conjugated rhein was 3.14+/-1.56% and 38.21+/-18.87% of dose, respectively, 48 h after dosing at 500 mg/kg of Onpi-to in male rats. The cumulative biliary excretion of rhein was 1.34+/-0.44% of dose 48 h after dosing at 500 mg/kg of Onpi-to in male rats.

Administration, Oral↗

PubMed2003

Effects of 17 beta-estradiol and the Japanese herbal medicine Keishi-bukuryo-gan on the release and synthesis of calcitonin gene-related peptide in ovariectomized rats.

The purpose of this study is to clarify the effects of 17beta-estradiol and the Japanese herbal medicine Keishi-bukuryo-gan on the release and synthesis of calcitonin gene-related peptide (CGRP) in ovariectomized (OVX) rats. The effect of ovariectomy on the release or synthesis was evaluated by measuring CGRP concentration in plasma after capsaicin (1.0 mg/kg, i.p.) injection or by measuring CGRP concentration and its mRNA expression in dorsal root ganglia in OVX rats. Ovariectomy attenuated the capsaicin-evoked increase in plasma concentration of CGRP, which was restored by treatment with 17beta-estradiol (0.010 mg/kg, s.c.) or Keishi-bukuryo-gan (1000 mg/kg, p.o.) for 7 days after ovariectomy. However, no significant differences were observed in the CGRP concentration and the mRNA expression of dorsal root ganglia by treating the rats with ovariectomy, 17 beta-estradiol, and Keishi-bukuryo-gan. These results suggest not only that estrogen deficiency attenuates CGRP release but also that 17beta-estradiol or Keishi-bukuryo-gan normalizes the attenuated release process.

Animals↗

PubMed2002

Liposomes possess drastic capabilities for topological transformation.

Morphological and topological changes of biological membranes play essential roles in cellular activities. It has been thought that these transformations are made possible through interactions with proteins. However, direct observation of giant liposomes by optical dark-field microscopy reveals that the lipid bilayer itself possesses the ability to undergo topological transformation.

Animals↗

PubMedDate not supplied

Pharmacokinetics of TJ-8117 (Onpi-to), a drug for renal failure (I): Plasma concentration, distribution and excretion of [3H]-(-)epicatechin 3-O-gallate in rats and dogs.

TJ-8117 (Onpi-to) is an herbal medicine extracted from a mixture of five crude medicinals (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), which has been developed as a drug for chronic renal failure. (-)Epicatechin 3-O-gallate (ECG), one of the active components of TJ-8117, was labeled with tritium and added to TJ-8117. Pharmacokinetics in plasma, tissue distribution and excretion of radioactivity were investigated following a single oral administration of TJ-8117 containing [3H]ECG ([3H]TJ-8117) in rats and dogs. 1. Following oral administration of [3H]TJ-8117, radioactivity exhibited linear pharmacokinetics in Cmax. Linearity of AUC(0-72 h) was lost at the highest dose of [3H]TJ-8117. Cmax and AUC(0-72 h) were higher in female rats than in male rats, a finding which suggested a sex difference in rats. Plasma levels of radioactivity displayed curves with one peak in dogs, which suggested a species difference between rats and dogs. 2. No accumulation was observed in any tissues in male rats. 3. Within 168 h after administration of [3H]TJ-8117 to male rats, 18.7%, 84.1% and 0.9% of the dose was excreted in urine, feces and expired air, respectively. Data from bile-duct cannulated rats indicated that at least 18.4% of the dose was absorbed.

Animals↗

PubMedDate not supplied

Pharmacokinetics of TJ-8117(Onpi-to), a drug for renal failure (II): effects of food, repeated administration and renal failure to plasma concentration of [3H]-(-)epicatechin 3-O-gallate in rats.

TJ-8117 (Onpi-to) is a herbal medicine extracted from mixture of five crude drugs (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), which has been developed as a drug for chronic renal failure. (-)Epicatechin 3-O-gallate (ECG), one of the active compounds of TJ-8117, was labeled with tritium and spiked to TJ-8117. Effects of food, renal failure and repeated administration to pharmacokinetics of ECG-related radioactivity in the plasma were investigated after oral administration of TJ-8117 containing [3H]ECG ([3H]TJ-8117) in male rats. After oral administration of [3H]TJ-8117, the radioactivity in the plasma in non-fasted rats was higher than that in fasted rats. AUC(0-72 h) and Cmax in the non-fasted was 123% and 248% of those in the fasted. After oral administration of [3H]TJ-8117, the radioactivity in the plasma in 5/6 nephrectomized rats was higher than that in sham-operated rats. AUC(0-72 h) and Cmax in 5/6 nephrectomized was 332% and 236% of those in sham-operated. After repeated administration of TJ-8117 for 6 days, [3H]TJ-8117 was administered on 7th day. Radioactivity in plasma in first day was similar to that in 7th day. The pharmacokinetic parameters were not significantly different between single and repeated administration.

Animals↗