Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
21 巻 , 8 号
選択された号の論文の23件中1~23を表示しています
  • Masanori YOSHIZUMI, Tetsuya KITAGAWA, Yuichi OZAWA, Kazutoshi TANO, Ko ...
    1998 年 21 巻 8 号 p. 787-791
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    In orther to elucidate the pharmacological properties of the formation of sulfoconjugated catecholamines (CAs) in human plasma, we investigated the changes in the plasma levels of free and sulfoconjugated CA during the continous infusion of dopamine (DA; 4-6 μg/kg/min for 24 h, followed by 3-4 μg/kg/min for 48 h) in patients who had undergone cardiac surgery. The plasma level of free DA increased immediately after the start of the infusion and reached a plateau within 1 h at a level of about 2000 times the basal value. In the control patients who had received non-cardiac surgery without DA infusion, plasma-free DA increased only 5-fold after their operation.The plasma level of DA sulfate increased linearly for 24 h, to 48-fold of the basal value by DA infusion, whereas it showed only a 2-fold increased in the contorl patients. After 24 h, due to reduction of the infused DA dose, the level of free DA gardually decreased, whereas the level of DA sulfate remained elevated. The plasma levels of free adrenaline (Ad) and noradrenaline (NA) also increased during the DA infusion, but their levels reached a plateau within 1-2 h. Sulfoconjugated Ad and NA increased progressively until the tapering off of DA infusion. In the control patients, both free and conjugated Ad and NA showed transient increases over 12 h after surgery. These results suggest that sulfoconjugation plays a role in regulating the plasma levels of excess free CA, therby modifying the cardiovascular effects of circulating CA. Measurement of the increaes in plasma conjugated CA may be useful as an index of the increase in free CA in plasma due to the administration of an exogenous form or release of endogenous CA from the tissues.
  • Yukiko HATA, Leonora Rivera PANCHO, Hiroshi NOJIMA, Ikuko KIMURA
    1998 年 21 巻 8 号 p. 792-794
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    The mechanism of potentiation of prostaglandin (PG) F-induced contraction of mouse mesenteric veins by (±)-[6]-gingerol was investigated in vitro. (±)-[6]-Gingerol (0.3 mM) potentiated the maximal contraction response elicited by PGF (0.28 mM) in the presence of intact vascular endothelium, but not in its absence (de-endothelialized preparations). The potentiating effect was completely inhibited by cyclooxygenase inhibitors (0.2 mM aspirin and 0.2 mM indomethacin) and partly by calcium antagonists (2 μM verapamil, 8 nM nitrendipine and 1 μM ryanodine), but not inhibited by nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor and ONO-3708, a thromboxane (TX) A2 antagonist. The potentiation by (±)-[6]-gingerol is also observed in mesenteric veins of streptozotocin-diabetic mice where the enhancement of PGF-induced contraction is caused mainly by activation of lipoxygenase. The potentiaion of PGF-induced contraction by (±)-[6]-gingerol may be caused by a cyclooxygenase-dependent release of vasoconstrictors, other than PGF and TXA2, or by inhibiting vasorelaxants released from endothelial cells of mouse mesenteric veins.
  • Atsushi GOHSHI, Kenji HONDA, Koji TOMINAGA, Yukio TAKANO, Toshiro MOTO ...
    1998 年 21 巻 8 号 p. 795-799
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    We examined ACTH release from cultured anterior pituitary cells of streptozotocin (STZ)-induced diabetic rats. Rats 1 week after the injection of STZ (55 mg/kg, i.v.) were used as a short-terms diabetic model, while rats 8 weeks after the injection of STZ were used as a long-term diabetic model. ACTH release induced by corticotropin-releasing factors (CRF) was significantly increased in the short-term diabetic rats, whereas ACTH release decreased in the long-term diabetic rats. A stimulator of adenylate cyclase, forskolin, caused marked increases in ACTH release in short-term diabetic rats, whereas it did not affect the long-term diabetic rats. An L-type Ca2+ channel agonist, BAY K 8644, did not affect ACTH release in the short-term diabetic ras, although it decreased ACTH release in long-term diabetic rats. In addition, CRF-induced ACTH release also increased in normal anterior pituitary cells cultured under high glucose conditions (25 mmol/l) for 5d.These results suggest that the increase in teh CRF-induced ACTH release from cultured anterior pituitary cells of short-term diabetic rats appears to involve the cAMP system in part. In contrast, the decrease in the CRF-induced ACTH release from the cultured anterior pituitary cells of long-term diabetic rats may indicate a change in the properties of the L-type Ca2+ channel coupled with the CRF receptor, or in the CRF receptor itself.
  • Norio HASHIMOTO, Toshihiko KURO, Katsuya FUJITA, Satoshi AZUMA, Yasuo ...
    1998 年 21 巻 8 号 p. 800-804
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    The pathophysiological role of endothelin ETB receptor-mediated action on systemic and renal hemodynamics and urine formation in deoxycorticosterone acetate (DOCA)-salt hypertensive rats was investigated. An intravenous bolus injection of a selective ETB receptor antagonist, BQ788 (1 mg/kg), produced a significant increase in mean arterial pressure (MAP) of DOCA-salt treated rats, whereas the agent-induced increase in MAP was less marked in normotensive sham rats. Administration of BQ788 caused a significant and sustained reduction in renal blood flow both in DOCA-salt and sham rats. No marked effects were observed on urine formation in both groups. Alternatively, a selective ETA receptor antagonist, FR139317 (10 mg/kg), produced a potent hypotensive effect, accompanied by significant renal vasodilation in DOCA-salt hypertensive rats, but these effects were partially reversed by the subsequent administration of BQ788. When renal perfusion pressure was protected from FR139317-induced hypotension by an aortic clamp, significant diuresis and natriuresis were observed, events partially reversed by the subsequent administration of BQ788. Our results indicate that the ETB receptor-mediated action tonically functions as a hypotensive and a renal vasodilatory factor and that these effects seem to be up-regulated in DOCA-salt hypertension. We also suggest that the ETA receptor blockade in DOCA-salt hypertensive rats unmasks the ETB receptor-mediated action which partially contributes to the antihypertensive effect induced by FR139317.
  • Yoshihiro SAITO, Masahiro HONDA, Masahiko CHIKUMA
    1998 年 21 巻 8 号 p. 805-808
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    Heparin-selenocystamine conjugate, which was intended to mimic the heparin-selenoprotein P complex, was prepared. The conjugate had glutathione peroxidase-like activity and activity was observed toward hydrogen peroxide, tert-butyl hydroperoxide, and cumene hydroperoxide. The ultraviolet spectrum of an aqueous solution of the conjugate was stable and had a similar shape to that observed transiently when selenocystamine was reduced by sodium cyanoborohydride; this suggests that the diselenide bond of selenocystamine introduced into heparin was cleaved during conjugate preparation and the selenol group is preserved. The conjugated reacted to the same degree as cysteine with 5, 5'-dithiobis (2-nitrobenzoic acid) (DTNB) releasing thionitro-benzoic acid, which indicated that the selenium in the conjugate is present as selenol. However, the reaction rate of the conjugate was slower than cysteine which may be due to partially restricted access of DTNB to the selenol group in the conjugate. This conjugate had 1, 1-diphenyl-2-picryl-hydrazyl(DPPH) radical scavenging activity as well as superoxicde anion scavenging activity. These results indicate that the conjugate serves as a useful model compound with a stable selenol group having a range of biological activities, and suggest a possible antioxidant defensive role for the complex of endogenous heparin-like substance and selenoprotein P.
  • Hiroshi SHIMODA, Hisashi MATSUDA, Johji YAMAHARA, Masayuki YOSHIKAWA
    1998 年 21 巻 8 号 p. 809-813
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    Immunomodulatory activities of constituents isolaetd from Hydrangeae Dulcis Folium and their related compounds on lymphocyte proliferation were investigated using splenocytes and lymph node cells. Thunberginol A (TA) significantly suppressed B lymphocyte proliferation stimulated by lipopolysaccharide (LPS) at 10-5M.However TA at a lower concentration (10-6M) and the other compounds, except hydrangenol and 3'-hydroxyhydrangeaic acid, tended to potentiate B lymphocytes proliferation (10-5M). On the other hand, thunberginol A significantly suppressed T lymphocyte proliferation stimulated by concanavalin A (Con A), but did not suppress phytohemagglutinin (PHA). Hydrocortisone and cyclosporin A strongly suppressed T lymphocyte proliferation induced by both Con A and PHA. These results suggest that thunberginol A acts on both B and T lymphocytes and may have a suppressive mechanism different from the knwon immunosuppressants. The cytotoxicity of TA for splenocytes seemed weaker than known immunosuppressants resulting from viability tests using MTT assay and the measurement of lactate dehydrogenase (LDH) released in the medium. MOreover, TA suppressed antigen-specific T lymphocyte proliferation in mice lymph node cells immunized with keyhole limpet hemocyanin (KLH). Thus, these findings show that TA has a suppressive effect on lymphocyte activation, and this inhibitory effect of TA seems to contribute to its suppressive effect on type IV allergies.
  • Masato FUKUTAKE, Shigeru YOKOTA, Hideki KAWAMURA, Akira IIZUKA, Sakae ...
    1998 年 21 巻 8 号 p. 814-817
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    This study was conducted t obtain effective cancer chemopreventive agents with low toxicity from medicinal herbs. The effect of aqueous extracts from 9 medicinal herbs with anti inflammatory effect were examined on the formation of azoxymethane (AOM)-induced aberrant crypt foci (ACF), putative preneoplastic lesions of the colon. Male F344 rats were treated with 15 mg/kg body weight of AOM once a week for two weeks. Herbal extract consisting of 2% of the diet was administered from 1 d prior to the first carcinogen treatment. The number of AOM-induced ACF per colon was counted at 4 week. Extracts of Coptidis Rhizoma and Scutellariae Radix significantly inhibited AOM-induced ACF formation. The number of ACF was decreased to 54% and 78% of that of the control by 2% Coptidis Rhizoma and Scutellariae Radix extract in the diet, respectively. Berberine and Baicalin, major ingredients of Coptideis Rhizoma and Scutellariae Radix, inhibited ACF formation at a dose equivalent to the amount in each herbal extract.Therefore, to investigte the mechanisms of action of berberine and baicalein which is the active substances of orally administered baicalin, their effects on cyclooxygenase 1 and 2 activities were studied. Berberine was found to inhibit cyclooxygenase 2 activity without inhibition of cyclooxygenase 1 activity, and baicalein inhibited cyclooxygenase 1 activity.Thus, Coptidis Rhizoma and Scutellariae Radix suppressed experimental colon carcinogenesis, and their chemopreventive effects were explained from the inhibition of berberine on cyclooxygenase 2 activity and baicalein on cyclooxygenase 1 activity.
  • Kazuyuki SHIMIZU, Yosie MAITANI, Noriko TAKAHASHI, Kozo TAKAYAMA, Tsun ...
    1998 年 21 巻 8 号 p. 818-822
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    Dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Ch) liposomes containing a soybean-derived sterylglucoside mixture (SG) (SG-liposomes) are effective for targeting hepatocytes in mice. We investigated uptake of SG-liposomes to hepatocytes compared with that via the galactose receptor. The association of SG-liposomes entrapping calcein was examined at 4°Cor 37°C, changing incubation time and the SG concentration of the liposomes, and using the inhibitor on the galactose receptor in rat primary cultured hepatocytes. The amount of liposomes recovered with hepatocytes was determined by measuring the concentration of calcein and imaged with confocal laser scanning microscopy in the cultured cells. The association of SG-liposomes at 4°C was significantly decreased compared with that at 37°C as that of liposomes containing lactosylceramide (LC) (LC-liposomes) that were already known to be taken up by hepatocytes via the asialogycoprotein receptor. While the association of SG-liposomes at both 4°C and 37°C increased with the increase of incubation time, the association of SG-liposomes at 37°C was almost saturated after 1 h. The association of SG-liposomes pretreated with concanavalin A was significantly decreased (to about 40% of that without pretreatment at 37°C) and was at the same level as the association of SG-liposomes and non-SG-liposomes at 4°C. The association of the SG-liposomes by hepatocytes incubated for 1 h at 37°C was almost saturated at about 2.0 nmol SG/mg protein. The association of the SG-liposomes with hepatocytes was not inhibited in the presence of LC-liposomes. The affinity of the galactose residue for hepatocyts appeared to be similar to that of the glucose residue in the liposomes, because the amount of sugar residue and the association of SG-liposomes and LC-liposomes were slmost the same values. These results suggest that SG-liposomes may be associated with hepatocytes not by a galactose receptor-mediated endocytosis.
  • Masayuki TAKAHARA, Akiko KUSANO, Makio SHIBANO, Genjiro KUSANO, Kenzo ...
    1998 年 21 巻 8 号 p. 823-828
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    The in vitro antimalarial activity against human malaria parasite (Plasmodium falciparum, FCR-3 strain) was examined using 59 triterpenoids obtained during studies on teh triterpenic constituents of Cimicifuga spp. The 50% effective concentration values (EC50) of 25 active triterpenoids were 1.0-3.0 μM, and 19 of the compounds had a common 16, 23 : 23, 26 : 24, 25-triepoxy group in the side-chain moieties. Among the active triterpenoids. 9 also showed significant inhibition of nucleoside transport in mouse spleocytes A relationship between the antimalarial, activity and the inhibition of nucleoside transport involving these triterpenoids is discussed.
  • Katsuhiro YAMASAKI, Masami NAKANO, Takuya KAWAHATA, Haruyo MORI, Toru ...
    1998 年 21 巻 8 号 p. 829-833
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    The anti-HIV-1 activity of aromatic herbs in Labiatae was evaluated in vitro. Forty five extract from among 51 samples obtained from 46 herb species showed significant inhibitory effects against HIV-1 induced cytopathogenicity in MT-4 cells. In particular, the aqueous extracts of Melissa officinalis, a family of Mentha×piperita "grapefruit mint", Mentha×piperita var. crispa, Ocimum basilicum cv "cinnamon", Perilla frutescens var. crispa f.viridis, Prunella vulgaris subsp. asiatica and Satureja montana showed potent anti-HIV-1 activity (with an ED of 16μg/ml). The active components in the extract samples were found to be water-solubel polar substances, not nonpolar compounds such as essential oils. In addition, these aqueous extracts inhibited giant cell formation in co-culture of Molt-4 cels with and without HIV-1 infection and showed inhibitory activity against HIV-1 reverse transcriptase.
  • Takao KONOSHIMA, Midori TAKASAKI, Harukuni TOKUDA, Hoyoku NISHINO, Ngu ...
    1998 年 21 巻 8 号 p. 834-838
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    Seven saponins (1-7) isolated from the rhizomes and roots of Panax vietnamensis were tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) induced by the tumor promoter, 12-O-tetrade-canoylphorbol-13-acetate (TPA), in Raji cells as a primary screening test for anit-tumor-promoters (cancer chemopreventive agents). The ocotillol-type saponin, majonoside-R2 (2), which is the major and characteristic constituent of this palnt, exhibited a significant inhibitory effect on EBV-EA activation. Furthermore, the cell cycle analysis of 2 on Raji cells was also examined and strong inhibition was observed on the effect of the cell cycle induced by TPA. Compound 2 showed potent anti-tumor-promoting activity in two-stage carcinogenesis tests of mouse skin using 7, 12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA or fumonisin B1 as a promoter. Consequently, these results suggest that majonoside-R2 (2) could be a valuabel chemopreventive agent against chemical carcinogenesis.
  • Loreto ALVAREZ-CEDRON, Francisco G. LOPEZ, Jose M. LANAO
    1998 年 21 巻 8 号 p. 839-843
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    A study has been carried out to characterize the binding of doxorubicin to hear homogenates and subcellular fractions. The technique chosen to perform the study was equilibrium dilalysis and the levels of anthracycline in the samples obtained from the dialysis were assessed using HPLC. Doxorubicin has high affinity to heart homogenates and subcellular fractions such as nuclear, mitochondrial and microsomal. The binding was saturable and dose-dependent. Doxorubicin binding is decreased in the presence of digoxin and especially verapamil.
  • Kazunori UENAKA, Toshiko KOUE, Tetsushi IWAI, Masahiko SHIBAKAWA, Kazu ...
    1998 年 21 巻 8 号 p. 844-846
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    We analyzed mexiletine in Japanese patients using populaiton pharmacokinetics. 139 serum concentration data, which were collected for therapeutic drug monitoring from 121 patients, were used for this analysis. We also investigated influence of age and gender on pharmacokinetics, and age was found to be an influential factor on clearance. The final pharmacokinetic parameters are, CL/F=0.580-0.00369·AGE (l/h/kg) and Vd/F=6.63 (L/kg). These results shoulds be useful for adjusting the dosage to a patient's age for the prevention of an adverse reaction caused by overexposure.
  • Koji TANIKAWA, Yoshiaki MATSUMOTO, Mitsuo MATSUMOTO, Masamichi FUKUOKA
    1998 年 21 巻 8 号 p. 847-852
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    MDGP, a computer program for population pharmacokinetics, has been developed. This program is based on maximum likelihood estimation with poly-dimensional normal distribution errors, and variable metric methods, direction set methods, conjugate gradient methods and the polytope method are provided as minimizations of objective function. The source codes of MDGP are described using ANSI C language. MDGP is able to run on wide platforms equipped with an ANSI C compiler. Users can use algebraic, ordinary differential and Laplace-transformed equations as descriptions of a pharmacokinetic model. Partial differential equations for each model parameter are not needed. Comparison of the estimated parameters, the iteration counts until convergence and objective function value, using MDGP and NONMEM, revealed that the calculation performance of the two programs are comparable.The MDGP is through to be useful for the analysis of various pharmacokinetic models, including population pharmacokinetic analysis.
  • Makoto TANAKA, Etsuhisa KUWAHARA, Masahiro TAKAHASHI, Osamu KOYAMA, No ...
    1998 年 21 巻 8 号 p. 853-857
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    The influence of bases and additives in the formulation for rectal absorption of amphotericin B (AMB) lyophilized with dipotassium glycyrrhizinate (GLYK) ws investigated using rabbits in relation to an in vitro release test. The release of AMB from the fatty base of Witepsol or a medium chain triglyceride (MCT) was markedly faster than that from the hydrophilic base of macrogol. The addition of polyoxyethylene (2) lauryl ether (POE(2)LE) into the fatty bases led to a marked increase in the release rate, wherease POE(9)LE or sodium lauryl sulfate resulted in a significantly lower release rate. Animals received rectally each of seven AMB formulatins of Witepsol H-15, macrogol, MCT with surfactants and aqueous solution. The absorption of the AMB lyophilized mixture with GLYK at a 1 : 9 molar ratio from a MCT base was significantly superior to that from macrogol. The addition of POE(2)LE into the MCT base resulted in a marked increase in bioavailability, showing the highest bioavailability of 4.9%. High serum levels of over 100 ng/ml of serum were maintained for 24 h following administration. The lowest bioavailability was 0.32% for the macrogol suppository. There was a good correlation between the release rate of AMB from the formulations and bioavailability. These results suggest that an AMB rectal formulation may provide a promising therapeutic alternative to infusion, taking into account the serum level of AMB exceeding the minimal inhibitory concentration of the infecting organism.
  • Junko ISHIZAKI, Koichi YOKOGAWA, Emi NAKASHIMA, Shoji OHKUMA, Fujio IC ...
    1998 年 21 巻 8 号 p. 858-861
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    Although basic drugs are distributed wiedely in various tissues, they are characteristically concentrated in the lung granule fraction. We examined the uptake of seven lipophilic basic drugs into rat lung granule fraction (P2) in vitro and investigated the contributions of drug lipophilicity and lysosomal trapping to the characteristic lung P2 distribution. The uptake of each drug into P2 was examined at various pH values. The drug concentration in P2 was determined by gas chromatography. Biperiden (BP) was rapidly taken up into P2, reaching a maximal concentration within 1 min at pH 7.4 at both 4°Cand 37°C. Both BP and chlorpromazine uptake into P2, was biphasic. Though the uptake rates of the seven drugs into P2 increased with rising pH, the rate of increase varied for each drug. There was a good correlation between the octanol-water partition coefficient of the non-ionized form (Poct) of each drug and the uptake into P2 in the presence or absence of NH4Cl, which inhibits lysosomal tarpping. However, uptake into P2 in the presence of NH4Cl showed a stronger Poct-dependency. We conclude that the distribution of basic drugs into lung P2 is dependent on both drug lipophilicity and lysosomal uptake.
  • Taeko ANDO, Yoshie MAITANI, Tomonaga YAMAMOTO, Kozo TAKAYAMA, Tsuneji ...
    1998 年 21 巻 8 号 p. 862-865
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    The effect of a soybean-derived sterol mixture (SS) and a steryl glucoside mixture (SG) as enhancers of the nasal absorption of insulin in rabbits was investigated. SS consists of β-sitosterol (Sit), campesterol (Camp), stigmasterol (Stig) and brassicaterol (Bras), and SG is a mixture of their monoglucosides. For each component of SS tested for efficacy in promoting the systemic absorption of nasally administered insulin, the following order was observed : Sit≩Camp>Stig. This finding was in agreement with the order of the enhancers' lipophilicity. In the case of SG, the effect of β-sitosterol β-D-glucoside (Sit-G) was significantly greater than that of SG. The pharmacological bioavailability was 6.7% for SG and 11.3% for Sit-G in the suspension dosage forms SG showed a greater degree of enhacment of insulin permeation through the nasal mucosa than SS. To elucidate the contribution of SG to the enhanced absorption, inslin permeation through an artificial membrane and the nasal mucosa was investigated in vitro, and the results were compared with those for SS. The findings suggest that SG and SS have some effect on nasal mucosa lipids.
  • Tomonaga YAMAMOTO, Yoshie MAITANI, Taeko ANDO, Koichi ISOWA, Kozo TAKA ...
    1998 年 21 巻 8 号 p. 866-870
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    A soybean-derived steryglucoside mixture (SG) is a potential enhancer of the nasal absorption of insulin.The aim of the study was to examine the absorption of insulin given as the powder dosage form with SG and excipient and to determine the subchronic effects of SG on the morphology of rabbit nasal epithelium. The insulin powder dosage form with SG was administered to the rabbit nasal cavity for five successive days. The average bioavailability and the average pharmacological bioavailability of insulin were about 25.0 and 61.6% respectively. The nasal mucosa was taken from the nasal cavity and side-effects were investigated using an optiphoto light microscope. The insulin powder dosage form with SG produced no signs of inflammation, erosion or squamous metaplasia. These findings indicate that SG can be considered as a safe and effective enhancer and excipient in the nasal insulin powder dosage form.
  • Jian GU, Hiroaki YUASA, Yayoi HAYASHI, Jun WATANABE
    1998 年 21 巻 8 号 p. 871-873
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    The first-pass intestinal metabolism of 5-fluorouracil (5-FU) was investigated by single-pass perfusion of the rat small intestine. At the low concentration of 0.06 mg/ml, the fraction of 5-FU absorbed into (i.e., appeared in) the meenteric venous blood (Fa, b was about 50% smaller than the fraction absorbed (disappeared) from the intestinal lumen (Fa), indicating the first-pass extraction of 5-FU in the intestinal mucosa. By addition of uracil (6 mg/ml), the Fa of 5-FU was reduced presumably by competition for the pyrimidine carrier at the process of intestinal uptake (entry into the mucosa). The Fa, b was also reduced, but to a lesser extent, resulting in insignificant first-pass extraction. These results suggest that the extraction of 5-FU in the absence of uracil is caused by metabolism and that uracil is a competitor for this pathway. When 5-FU concentration was reiased from 0.06 to 0.6 mg/ml in the absenec of uracil, the Fa was reduced by about 50%, consistent with the suggestion of the involvement of saturable uptake by the pyrimidine carrier, and thereafter remained unchanged at 6 mg/ml. Howeve, since Fa, b was also reduced by a similar extent, the intenstinal availability (F1=Fa, b/Fa) was unchanged at about 0.5, indicating that the intestinal first-pass extraction of 5-FU is independent of concentration with the extraction ratio (difference between unity and F1) of about 0.5 over the wide range of concentration from 0.06 to 6 mg/ml. Thus, the present study demonstrates that the significant first-pass metabolic extraction of 5-FU occurs in the mucosa of the small intestine, supporting our previous suggestion that 5-FU undergoes first-pass metabolism not only in the liver but also in the small intestine after oral administration. Considering that the oral bioavailability of 5-Fu in the human (28%) is reportedly comparable with that in the rat (28%), it is likely that intestinal first-pass metabolism may be significant also in the human. Intestinal first-pass metabolism should be taken into account to explore more efficient and controlled oral 5-FU therapy.
  • Tadashi YAMADA, Yukio KATO, Hiroyuki KUSUHARA, Michel LEMAIRE, Yuichi ...
    1998 年 21 巻 8 号 p. 874-878
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    The cyclic cationic octapeptide octreotide is known to be taken up by hepatocytes, with more than 70% of an intravenous dose being excreted into bile in unchanged form. We have already reported that a transporter other than the canalicular multispecific organic anion transporter (cMOAT) is responsible for the biliary excretion of octreotide in vivo. The aim of this study is to obtain an insight into the transporter of octreotide in bile canalicular membrane. The effect of various compounds on the ATP-dependent uptake of octreotide by rat bile canalicular membrane vesicles (CMV) was investigated. The ATP-dependent uptake of [14C] octreotide by CMV was inhibited by verapamil, vincristine and PSC833 in a concentration-dependent manner, tha maximum inhibitory effects of these compounds being almost equal to that of excess unlabeled octreotide, while taurocholic acid (TCA) caused no inhibition at concentrations much higher than the Km of TCA uptake by CMV. Mutual inhibition between octreotide and dinitrophenylglutathione (DNP-SG), a representative substrate for cMOAT was only minor and could only be observed at concentrations much higher than the Km for each ligand uptake. To examine the contribution of P-glycoprotein to the biliary excretion of octreotide in vivo, biliary excretion of octreotide was compared between P-glycoprotein-induced rats by phenothiazine (PTZ) treatment and normal rats. A significant increase in the biliary excretion rate was observed in PTZ-treated rats. Only a slight decrease in biliary excretion was observed in mdr1a knock-out mice compared with noraml mice, which may be explained by the associated induction of mdr1b. These results demonstrate that the transporter for octreotide is different from cMOST and the bile acid transporter. The involvement of P-glycoprotein in the biliary excretion of octreotide is suggested.
  • Shuhei ISHIKURA, Yutaka YAMAMOTO, Kazuya MATSUURA, Jianjun WEI, M.E. H ...
    1998 年 21 巻 8 号 p. 879-881
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    We previously cloned a cDNA for mouse cerebellum carbonyl reductase which shows more than 81% homology to the cDNAs for monomeric carbonyl reductases of the rat, rabbit and human, and for pig 20β-hydroxy-steroid dehydrogenase. In the present study, we expressed the recombinant monomeric enzyme (34 kDa and pI 8.3) from the cDNA and compared its properties with the recombinant human enzyme. The mouse and human enzymes showed similar functional properties, although they differed in kinetic constants for carbonyl substrates and in inhibitor sensitivity. Both enzymes lacked glutathione S-transferase activity. Western blot and reversetranscription-polymerase chain reaction analyses showed that the enzyme protein and its mRNA are expressed in various mouse tissues.
  • Terushi HASHIGUCHI, Akinori TAKADA, Atsutoshi IKESUE, Junji OHTA, Tosh ...
    1998 年 21 巻 8 号 p. 882-885
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    Prednisolone (PN) and an esterified derivative (PND) were evaluated in pharmacological and pharmacokinetic studies. The pharmacological study was performed using a rat croton-oil induced ear edema model. The results for the topical effect in skin and the systemic effect through multiple topical applications showed that PN and PND were equally potent in suppressing edema, and that PN caused a reduction in thymus weight, whereas PND had little effect.The concentration of these steroids in hairless mouse skin was estimated from an in vitro percutaneous absorption study using the computer simulation program MULTI(FILT). PND was found to be poorly absorbed. In fact, the PND concentration in the viable skin remained low (0.79 μg/cm2), even after 7d. However, the estimated concentration of PND in the viable skin appears to be in excess of the threshold for effective topical effect during the pharmacological evaluation. In contrast, in the case of PN, the estimated PN concentration increased gradually after application and reached a level of 10.22 μg/cm2 at day 7, suggesting that this increase in PN concentration in the viable skin could result in a systemic effect.The difference between PN and PND concentration in the skin during the time course could be due to the metabolism of PND to PN in the viable skin. Consequently, the difference between the pharmacological study is reflected from the results of the pharmacokinetics of PN and PND in the skin.
  • Tsutomu MASUJIMA, Kayo IKEDA, Koichiro OZAWA, Atsushi TAMURA, Yumiko T ...
    1998 年 21 巻 8 号 p. 886-888
    発行日: 1998/08/15
    公開日: 2008/04/10
    ジャーナル フリー
    Particles of HPLC resins are used for the trapping of secreted molecules from a single cell. The basic molecules, e.g., histamine, are secreted from a single RBL-2H3 cell by granule exocytosis and are trapped by cation-exchange HPLC resins outside the cell. Since quinacrine is concentrated into the exoctotic and acidic micro-granules in RBL-2H3 cells, which are used as a model cell line of mast cells, we measured the change in the fluorescence intensity of the quinacrine released from the cells and that of molecules trapped on the resin using a videomicroscope. By measuring the increase in the fluorescence intensity of te resins, we can estimate the real time course of molecular secretion from a single cell.
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