研究者詳細 - 合葉　哲也

A study of the hydrophilic cellulose matrix: Effect of indomethacin and a water-soluble additive on swelling properties

Suwannee P. Panomsuk, Tomomi Hatanaka, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizumi

International Journal of Pharmaceutics 126 ( 1-2 ) 147 - 153 1995年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

A swelling measurement device was designed to observe the axial swelling direction of a matrix containing various types of hydrophilic cellulose derivatives (methylcellulose, hydroxypropylmethylcellulose and hydroxypropylcellulose). The effect of indomethacin and lactose on the swelling properties was also studied. The maximum swelling index and the apparent diffusion coefficient of water in the matrix, calculated from the swelling data, were used to describe the swelling properties of the matrix, reflecting the matrix integrity. The results showed that hydroxypropylcellulose produced a matrix with a high integrity. Indomethacin and lactose changed the swelling properties of the hydrophilic cellulose matrices in this study. © 1995.

DOI： 10.1016/0378-5173(95)04113-3

Effect of pH on the skin permeability of a zwitterionic drug, cephalexin

Tomomi Hatanaka, Setsuko Morigaki, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizumi

International Journal of Pharmaceutics 125 ( 2 ) 195 - 203 1995年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Skin permeability of the zwitterionic drug, cephalexin, was measured at various pH. A U-shaped curve was obtained for the relationship between the permeability coefficient and pH. Although cephalexin degraded dependent on the pH, the concentration in the suspended donor solution was maintained constant by the high dissolution rate. The barrier function of skin, which was assessed by the permeation of the nonelectrolytes, cortisone and o-mannitol, did not change over the range from pH 3.0 to 7.0. The permeability coefficient of cephalexin decreased with increase in zwitterion fraction and decrease in fractions of cation and anion, suggesting that each ionic species has different skin permeability. The permeability coefficient of zwitterion, estimated on this assumption of each ionic species having different permeability, was about 10% that of cation and anion. The octanol/buffer distribution coefficient and diffusion coefficient were also lower for zwitterion than for cation and anion. This suggests that the pH dependency in skin permeability of cephalexin may reflect the permselective property of skin dependent on the lipophilicity and/or diffusivity of ionic species. © 1995.

DOI： 10.1016/0378-5173(95)00113-W

Effects of probenecid and cimetidine on the renal excretion of 3’-azido-3’-deoxy-thymidine in rats 査読

Aiba T, Sakurai Y, Tsukada S, Koizumi T

Journal of Pharmacology and Experimental Therapeutics, 272(1): 94-99 272 ( 1 ) 94 - 99 1995年1月

A Study of the Hydrophilic Cellulose Matrix: Effect of Indomethacin and a Water-Soluble Additive on Release Mechanisms

Suwannee P. Panomsuk, Tomomi Hatanaka, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizum

Chemical and Pharmaceutical Bulletin 43 ( 6 ) 994 - 999 1995年

記述言語：英語掲載種別：研究論文（学術雑誌）

The release profile of indomethacin (IM) from a direct compressible matrix containing three hydrophilic cellulose derivatives, methylcellulose (MC25 and MC50), hydroxypropylcellulose (HPC140), and hydroxypropylmethylcellu-lose (HPMC50) was studied. The drug release profile was affected by matrix size, polymer type, drug: polymer ratio and water soluble additive (lactose). An IM zero-order release matrix can be obtained by mixture and direct compression with MC50, HPMC50 and HPC140. The release rate from the MC50 and HPC140 matrix can be modified by replacing MC50 or HPC140 with MC25, and a zero-order release could be obtained even when the amount of replacement with MC25 is up to 35 and 45%, respectively. Lactose up to 10% slightly affected the release profile. IM released from this kind of matrix by a zero-order rate seems to be controlled by the swelling and relaxation of the polymer. © 1995, The Pharmaceutical Society of Japan. All rights reserved.

DOI： 10.1248/cpb.43.994

Kinetic Analysis of Neuromuscular Blockade. I. Relationship between Twitch Depression and Stimulation Frequency after d-Tubocurarine Administration. 査読

田島武志, 金子和代, 畑中朋美, 合葉哲也, 片山和憲, 小泉保

Biological and Pharmaceutical Bulletin 17 ( 8 ) 1083 - 1088 1994年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：公益社団法人日本薬学会

The degree of twitch depression induced by nondepolarizing neuromuscular blocking drugs is known to be dependent on the stimulation frequency employed. Train-of-four (TOF) stimulations with different frequencies (0.67, 1.33 and 2.0Hz) were delivered to a sciatic nerve of a rat and series of four twitch heights of a tibialis anterior muscle were measured after d-tubocurarine (d-TC) administration. With a decrease of stimulus interval, twitch heights were intensely depressed. We hypothesized that the oservations are due to the changes of released amount of neuromuscular transmitter, acetylcholine, dependent on stimulus interval, and a pharmacokinetic/pharmacodynamic model based on the hypothesis was proposed. The model allowed simultaneous fitting of the twitch height depression after d-TC administration. It also could give a rationale to the fact that TOF stimulation at 2.0 Hz is a more sensitive monitoring method of neuromuscular function than single twitch stimulation (0.1-0.2 Hz).

DOI： 10.1248/bpb.17.1083

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Kinetic Analysis of Neuromuscular Blockade. II. Train-of-Four Fade Induced by d-Tubocurarine and .ALPHA.-Bungarotoxin. 査読

その他リンク： http://search.jamas.or.jp/link/ui/1995191748

田島武志, 加藤安宏, 畑中朋美, 合葉哲也, 片山和憲, 小泉保

Biological and Pharmaceutical Bulletin 17 ( 8 ) 1089 - 1093 1994年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：公益社団法人日本薬学会

The degree of train-of-four (TOF) fade, i.e., the reduction of the fourth to the first twitch height in a train, induced by d-tubocurarine (d-TC) and α-bungarotoxin (α-BX) was investigated. The fade induced by d-TC was pronounced in comparison with that by α-BX, and the difference was analyzed using a kinetic model. Based on the assumptions : (1) Acetylcholine (ACh) binds to the nicotinic receptor and evokes twitch response. (2) The amount of released ACh is dependent on stimulus interval. (3) d-TC interacts competitively with the receptor. (4) α-BX interacts irreversibly with the receptor. It was suggested that the fade by d-TC and α-BX can be explained by the difference of the receptor occupancy by ACh which was caused by different interaction mechanisms of the two muscle relaxants with receptors.

DOI： 10.1248/bpb.17.1089

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その他リンク： http://search.jamas.or.jp/link/ui/1995191747

Renal handling of tobramycin in the isolated perfused rat kidney 査読

Tetsuya Aiba, Yoshie Itoga, Hiromasa Shimizu, Yusuke Tanigawara, Ryohei Hori

Journal of Pharmaceutical Sciences 83 ( 5 ) 723 - 726 1994年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

The renal handling of tobramycin (TOB), an aminoglycoside antibiotic (AG), was studied using a single‐pass isolated perfused rat kidney with moment analysis. In the bolus administration study at tracer concentration (7.4 μM), 32% of the glomerular‐filtrated TOB remained in the lumen, but no TOB was found in the vein. This ratio of the luminal uptake was reduced in a dose‐dependent manner. Other aminoglycosides such as gentamicin inhibited this uptake, but tetraethylammonium and glucosamine had no effect. In addition, under the alkalinuria condition, TOB uptake was decreased to 67% of the control value. This indicated that TOB has mainly been taken into the renal epithelial cells from their luminal site and that this uptake process was saturable and specific for AGs which have more than one cationic group. The present findings should be helpful in developing a method to reduce the nephrotoxicity of AGs and to identify their toxicity mechanisms. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/jps.2600830526

Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney 査読

HORI R

J. Pharmacol. Exp. Ther. 266 ( 3 ) 1620 - 16258520/ 1993年3月

Effect of l-menthol on the permeation of indomethacin, mannitol and cortisone through excised hairless mouse skin 査読

片山和憲, 高橋修, 松井良幹, 森垣説子, 合葉哲也, 掛見正郎, 小泉保

Chem Pharm Bull 40 ( 11 ) 3097 - 3099 1992年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：公益社団法人日本薬学会

The effect of l-menthol on the skin permeability of mannitol, cortisone or indomethacin was examined by an in vitro penetration technique with hairless mouse skin. The donor solution was prepared with phosphate buffered saline, ethanol : buffered saline (20 : 80,v/v) or ethanol : buffered saline (20 : 80,v/v) containing 1% (w/v) l-menthol. Although ethanol showed little enhancing effect, l-menthol in an aqueous ethanol vehicle at pH 7.4 increased the permeability coefficients of mannitol and indomethacin by about 100 times that of the control (an aqueous vehicle) and increased that of cortisone by about 10 times. l-Menthol, however, scarcely enhanced the penetration of indomethacin at pH 3.0,the majority of the species being in unionized form. These results suggested that the menthol-ethanol-aqueous system enhanced skin permeability through a direct effect on the polar and/or lipid pathways, while the thermodynamic activity of the penetrant molecule in the delivery vehicle might also influence the effectiveness of the penetration enhancer.

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Moment analysis of drug disposition in kidney. II: Urine pH‐dependent tubular secretion of tetraethylammonium in the isolated perfused rat kidney 査読

Akira Kamiya, Yusuke Tanigawara, Yoshihiro Saito, Yoshie Hayashi, Tetsuya Aiba, Ken‐Ichi Inui, Ryohei Hori

Journal of Pharmaceutical Sciences 79 ( 8 ) 692 - 697 1990年

記述言語：英語掲載種別：研究論文（学術雑誌）

Effects of urine pH on the renal tubular secretion of an organic cation (tetraethylammonium, TEA) and an organic anion (p‐aminohippurate, PAH) were investigated using the isolated erythrocyte‐perfused rat kidney. The method was based on a multiple indicator dilution experiment and noncompartmental moment analysis. Treatment with sodium bicarbonate and sodium dihydrogen phosphate increased and decreased urine pH, respectively, but affected neither the condition of the perfused kidney nor the renal handling of albumin and inulin. In TEA studies, the increase of urine pH prolonged the mean residence time in renal epithelial cells (T̄cell) and reduced the apparent secretion intrinsic clearance, but did not influence the volume of distribution in the kidney (Vddrug). The decrease of urine pH did not affect these kinetic parameters. By contrast, PAH secretion was constant against the change of urine pH. Since any change in the basolateral membrane transport is reflected in Vddrug, the net transport from blood to cells can be regarded as similar under these treatments. On the other hand, the prolonged T̄cell of TEA with the increased urine pH suggested a slow transport from cells to lumen across the brush‐border membranes. The present results coincide with the hypothetical mechanism that organic cations are secreted via an active transport system, coupled to the countertransport of H+ into cells. In conclusion, the present method is useful to separately evaluate the transmembrane transport across both sides of the renal epithelial cells in a morphologically intact kidney. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/jps.2600790809

Moment analysis of drug disposition in kidney. III: Transport of p‐aminohippurate and tetraethylammonium in the perfused kidney isolated from uranyl nitrate‐induced acute renal failure rats 査読

Yusuke Tanigawara, Yoshihiro Saito, Tetsuya Aiba, Kou Ohoka, Akira Kamiya, Ryohei Hori

Journal of Pharmaceutical Sciences 79 ( 3 ) 249 - 256 1990年

記述言語：英語掲載種別：研究論文（学術雑誌）

A different manner of insufficiency of renal epithelial cell transport between the organic anion and cation, p‐aminohippurate and tetraethylammonium, respectively, was observed in the perfused kidney isolated from uranyl nitrate‐induced acute renal failure (ARF) rats. The single‐pass outflow pattern of the perfused kidney was analyzed by noncompartmental moment analysis. The active tubular secretion was impaired faster than the reduction of glomerular filtration, and the tetraethylammonium secretion decreased at an earlier stage of ARF than p‐aminohippurate. The apparent uptake rate constant from blood to cells of p‐aminohippurate was reduced with the progress of ARF and associated with the amount of this drug secreted, whereas the uptake rate constant of tetraethylammonium did not change until the late stage of ARF. The mean residence time in renal epithelial cells of tetraethylammonium was prolonged with reduction of the amount to be secreted, while that of p‐aminohippurate remained unchanged. Therefore, the uptake of p‐aminohippurate across the basolateral membranes decreased gradually, and the transport across the brush border membranes was still unchanged after uranyl nitrate treatment. On the other hand, the secretion of tetraethylammonium from cells to lumen was impaired at first, and then the uptake from blood to cells was impaired. These results suggest that impairment by uranyl nitrate‐induced ARF appears at the carrier‐mediated transport process of the epithelial cell membranes for both organic anions and cations. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/jps.2600790315

Moment analysis of drug disposition in kidney: Transcellular transport kinetics of p‐Aminohippurate in the Isolated Perfused Rat Kidney 査読

Ryohei Hori, Yusuke Tanigawara, Yoshihiro Saito, Yoshie Hayashi, Tetsuya Aiba, Katsuhiko Okumura, Akira Kamiya

Journal of Pharmaceutical Sciences 77 ( 6 ) 471 - 476 1988年

記述言語：英語掲載種別：研究論文（学術雑誌）

The mean renal epithelial cell residence time, T̄cell, was defined as a model‐independent characteristic of the transcellular transport process in the isolated perfused kidney. The transcellular transport process includes transport at the basolateral membrane, diffusion in the cytosol, and transport at the brush border membrane. The parameter T̄cell represents the mean time for the drug secreted from the tubules to pass through the renal epithelial cells, and is calculated as the difference of the mean urinary transit time between secreted drug and inulin in the single‐pass perfusion system. Therefore, the urinary excretion rate–time course is indispensable to evaluate T̄cell. p‐Amino‐hippuric acid was used as a model compound. The bovine erythrocytes in the perfusate kept the isolated kidney in an almost constant physiological condition, including secretion function. The renal vein outflow curves were also analyzed by the use of moments. The dispersion in the catheter was corrected by a deconvolution. The apparent secretion intrinsic clearance and the apparent volume of distribution were calculated from the moments. The present method will be useful for analysis of the transcellular transport mechanism and the effect of disease states on renal transport of drugs. Copyright © 1988 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/jps.2600770602