研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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Moment analysis of drug disposition in kidney. VI

He Yan Ling, Tanigawara Yusuke, Kamiya Akira, Hori Ryohei

Journal of Pharmacokinetics and Biopharmaceutics 19 （ 6 ） 667 - 690 1991年12月

ISSN 0090-466X

This paper describes a novel method to assess the antiluminal membrane (ALM) and luminal membrane (LM) transport in vivo across renal tubular epithelial cells. The method is based upon a noncompartmental moment analysis of the plasma concentration and urinary excretion rate curves following renal artery injection. Quantitative relationships are represented between the noncompartmental parameters (clearance, volume of distribution, and the mean transit time) and the first-order rate constants associated with transmembrane transport processes. The in vivo transepithelial transport of [¹⁴C]p -aminohippurate (PAH) was examined using the rat kidney in the absence or presence of various plasma concentrations of unlabeled PAH, cefazolin, and methotrexate. The tubular secretion intrinsic clearance was reduced with an increase in the plasma concentration of concurrent unlabeled organic onions. The distribution volume of PAH in the kidney decreased in association with a decrease in the amount of PAH secreted, whereas the mean transepithelial (artery-to-lumen) transit time (-T_cell) remained constant. These findings indicate that ALM transport is a capacity-limited process determining the amount of tubular secretion, and that LM transport is linear over the concentration range examined and independent of the amount of secretion. The contribution of ALM and LM transport to transcellular transport was first clarified in vivo. The present method will be useful for analyzing the transmembrane transport processes in vivo for highly diffusible substances in the kidney. © 1991 Plenum Publishing Corporation.

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Effects of counteranion of TRH and loading amount on control of TRH release from copoly(dl-lactic/glycolic acid) microspheres prepared by an in-water drying method

Toshiro Heya, Hiroaki Okada, Yusuke Tanigawara, Yasuaki Ogawa, Hajime Toguchi

International Journal of Pharmaceutics 69 （ 1 ） 69 - 75 1991年02月

ISSN 0378-5173

The preparation of injectable sustained release microspheres of TRH was investigated. The drug was encapsulated in copoly(dl-lactic/glycolic acid) (PLGA) using an in-water drying method through a w/o/w emulsion. The predominant factors influencing the entrapment ratio of TRH in the microspheres and the release rate of TRH from the microspheres were the loading amount and the dissociation state of the drug. Microspheres of TRH encapsulated as a free base at an adequate concentration provided a small initial burst followed by a zero-order prolonged release regardless of the high water solubility of the drug. The addition of strong acids to the inner aqueous phase interfered with the encapsulation efficacy and caused a large initial burst. The ionic interaction between the basic functional group of TRH and the carboxylic acid end group of PLGA during the preparation is necessary to produce a rigid matrix of the microspheres. This method is applicable to the microencapsulation of other water-soluble basic peptides in PLGA. © 1991.

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Moment analysis of drug disposition in kidney. V

Hori Ryohei, He Yan Ling, Saito Yoshihiro, Kamiya Akira, Tanigawara Yusuke

Journal of Pharmacokinetics and Biopharmaceutics 19 （ 1 ） 51 - 70 1991年02月

ISSN 0090-466X

A new method that can assess the kinetics of in vivo transepithelial transport in rat kidney has been established. The method is based upon a multiple-indicator dilution experiment and the moment analysis theory. After simultaneous bolus injections of p-aminohippurate (PAH) and inulin into the right renal artery, blood samples were taken from the carotid artery and urine was separately collected from right and left ureters. The characteristic response for the first passage of drugs through the right kidney was evaluated by taking blood circulation into consideration. To determine the mean artery-tovein transit time and the extraction ratio in the kidney, an intravenous injection was also performed as a reference experiment for deconvolution. The urinary excretion curve corresponding to the first passage was obtained as the difference between both kidneys. The mean artery-tolumen transit time (mean transepithelial transit time, -T_cell)was computed by subtracting the mean urinary transit time of inulin from that of secreted PAH. Sinc transport across the luminal membrane into the lumen from tubular epithelial cells can influence the cellular residence time of drugs, - T_celland the single-pass mean residence time in epithelial cells (-T_cell.sp)can be thought of describing luminal membrane transport. The value of -T_{cell obtained for 0. t mM PAH was 22 sec and it was prolonged to 61 sec in the presence of probenecid, suggesting an inhibitory effect on transport across the luminal membrane. On the other hand, antiluminal membrane transport into cells from blood is characterized by the volume of distribution in the kidney} (Vd_PAH). Vd_{PAH was remarkably decreased by treatment with probenecid, indicating an inhibitory effect on antiluminal membrane transport. The effects of probenecid on both sides of epithelial cell membrane transport were first demonstrated} in vivo. The present method is useful for the analysis of in vivo transepithelial transport including antiluminal and luminal membrane transport for drugs excreted via tubular secretion. © 1991 Plenum Publishing Corporation.

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Betamipronの腎毒性軽減作用とその作用機序（1）-腎組織輸送との関連-

長沼　英夫，常盤　弘，広内　康邦，川原　幸則，福重　潤一郎，深見　征治，広田　孝司，村松　重基，高萩　英邦，乾　賢一，谷川原　祐介，安原　眞人，堀　了平，桑原　章吾

Chemotherapy 39 （ SUPPL. 3 ） 166 - 177 1991年

ISSN 0009-3165

Mean residence time in organs in toxicokinetic studies

Tanigawara Y., He Y. L., Aiba T., Yasuhara M., Hori R., Hirouchi Y., Naganuma H., Kawahara Y., Okada R.

Journal of Pharmacobio-Dynamics 14 （ 2 ） 1991年

ISSN 0386-846X

Moment analysis of drug disposition in rat kidney

Saito Y., Tanigawara Y., Okamura N., Shimizu H., Kamiya A., Hori R.

Journal of Pharmacy and Pharmacology 43 （ 5 ） 311 - 316 1991年

ISSN 0022-3573

The determining step in transepithelial transport of p-aminohippurate (PAH) in renal tubular secretion has been elucidated in the rat isolated perfused kidney. The method was based upon a multiple indicator dilution experiment and non-compartmental moment analysis. Single-pass dilution curves were obtained from venous and urinary effluents after simultaneous intra-arterial injections of Evans blue with albumin, [³H]inulin and [¹⁴C]PAH. Probenecid was used as a transport inhibitor and dissolved in both perfusate and injection solution. The urinary excretion of PAH decreased depending on the probenecid concentration, while that of inulin was not affected. No correlation was observed between the amount of secretion and the mean residence time of secreted PAH in renal epithelial cells [T̄(cell)]. Since T̄(cell) ought to be affected by the rate of secretion from cells to lumen, it was suggested that the secretion rate was independent of the amount secreted. In contrast, the amount of PAH excreted via tubular secretion showed a linear correlation with the volume of distribution in the kidney and the apparent rate constant for tubular uptake of PAH. Since these kinetic parameters reflect the transport from blood into cells across the basolateral membranes of renal epithelial cells, the present results demonstrated that basolateral membrane transport is a determining step in the transcellular transport of PAH and that the major effect of probenecid is the inhibition of transport from blood into cells.

Effect of folinic acid on tissue residence and excretion of methotrexate in rats

He Y. L., Tanigawara Y., Yasuhara M., Hori R.

Drug Metabolism and Disposition 19 （ 4 ） 729 - 734 1991年

ISSN 0090-9556

The effect of folinic acid (CF) on the tissue residence and renal excretion of methotrexate (MTX) in the rat model is described in an experiment designed to resemble a clinical regimen of high-dose MTX therapy with CF rescue. Concentrations of MTX in the kidney, liver, and plasma were determined following the sequential killing of the animals up to 24 hr after an iv bolus injection of 100 μmol/kg MTX. The treated group received repeated iv doses of CF (5.86 μmol/kg) for 9.3 hr. The tissue retention property of MTX was characterized by noncompartmental parameters, the mean residence time (MRT), and the single-pass mean residence time (MRTSP) in organs. The values of MRT in the kidney and liver were greater than that in plasma and were shortened by the CF treatment, indicating that CF is effective in reducing the duration of exposure to MTX in those organs. For drugs whose duration of exposure is a key factor in their toxicity, MRTSP was shown to be a useful parameter in toxicokinetic study. The renal clearance of MTX was virtually constant over a wide range of plasma MTX levels (0.1-165 μM) and was inhibited by p-aminohippurate. CF accelerated the renal excretion of MTX, which effect depended on the plasma concentration of MTX. Since reabsorption and filtration were not affected by CF, the increased excretion of MTX was attributed to a stimulation of tubular secretion. These observations show that CF exerts a beneficial effect in accelerating the excretion of MTX residing in the organs, in addition to supplying active folate to aid the resumption of de novo DNA synthesis.

Pulmonary and hepatic disposition of hippuryl-L-histidyl-L-leucine

Tanigawara Y., He Y. L., Okumura K., Hori R.

Chemical and Pharmaceutical Bulletin 39 （ 3 ） 761 - 764 1991年

ISSN 0009-2363

Betamipronの腎毒性軽減作用とその作用機序（2）-腎排泄挙動との関連-

長沼　英夫，広内　康邦，川原　幸則，乾　賢一，谷川原　祐介，安原　眞人，堀　了平，桑原　章吾，

Chemotherapy 39 （ SUPPL. 3 ） 178 - 189 1991年

ISSN 0009-3165

日本人におけるPopulation Pharmacokinetic Parametersの推定　Ⅲ.フェニトイン

堀　了平，奥村　勝彦，北澤　式文，神代　昭，齋藤　侑也，樋口　駿，水柿　道直，山路　昭，力久　忠昭，谷川原　祐介

薬剤学 50 （ 3 ） 292 - 299 1990年

Pharmacokinetics in chimpanzees of recombinant human tissue-type plasminogen activator produced in mouse C127 and Chinese hamster ovary cells

Tanigawara Y., Hori R., Okumura K., Tsuji J. I., Shimizu N., N oma S., Suzuki J., Livingston D. J., Richards S. M., Keyes L. D., Co uch R. C., Erickson M. K.

Chemical and Pharmaceutical Bulletin 38 （ 2 ） 517 - 522 1990年

ISSN 0009-2363

Moment analysis of drug disposition in kidney. II

Kamiya A., Tanigawara Y., Saito Y., Hayashi Y., Aiba T., Inui K., Hori R.

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

ISSN 0022-3549

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 (T̄(cell)) and reduced the apparent secretion intrinsic clearance, but did not influence the volume of distribution in the kidney (Vd(drug)). 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 Vd(drug), the net transport from blood to cells can be regarded as similar under these treatments. On the other hand, the prolonged T̄(cell) 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 hypothelical 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.

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Moment analysis of drug disposition in kidney. III

Tanigawara Y., Saito Y., Aiba T., Ohoka K., Kamiya A., Hori R.

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

ISSN 0022-3549

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.

日本人におけるPopulation Pharmacokinetic Parametersの推定　Ⅱ.カルバマゼピン

堀　了平，奥村　勝彦，北澤　式文，神代　昭，齋藤　侑也，樋口　駿，水柿　道直，山路　昭，力久　忠昭，谷川原　祐介

薬剤学 49 （ 4 ） 304 - 312 1989年

Blood oxygen tension-related change of theophylline clearance in experimental hypoxemia

Kishimoto I., Tanigawara Y., Okumura K., Hori R.

Journal of Pharmacology and Experimental Therapeutics 248 （ 3 ） 1237 - 1242 1989年

ISSN 0022-3565

The effects of arterial blood oxygen tension on the pharmacokinetics of theophylline were investigated using an experimental acute hypoxemia model in rats. Conscious rats were exposed to hypoxic gas composed of 8% O₂-92% N₂. After blood gas tensions and blood pH were stabilized, rats received 5 mg/kg i.v. theophylline, and urine and blood samples were collected. The steady-state volume of distribution, unbound free fraction and hematocrit were unaffected by hypoxemia. Total body clearance was significantly changed (P<.01) from 0.156 ± 0.020 l/kg/hr in control to 0.0556 ± 0.0067 l/kg/hr in hypoxemic rats due to the reduction of both hepatic and renal clearances. In another constant rate i.v. infusion study, the plateau plasma concentration of theophylline was elevated steeply as soon as animals had inspired hypoxic gas, and the elevated concentrations went down after returning to room air. The present results suggested that the variation of arterial oxygen tension is one possible mechanism for a rapid and large intraindividual variability in theophylline clearance in acutely ill patients with chronic obstructive pulmonary disease.

日本人におけるPopulation Pharmacokinetic Parametersの推定　Ⅰ.バルプロ酸

堀　了平，奥村　勝彦，北澤　式文，神代　昭，齋藤　侑也，樋口　駿，水柿　道直，山路　昭，力久　忠昭，谷川原　祐介

薬剤学 49 （ 2 ） 148 - 156 1989年

Moment analysis of drug disposition in kidney

Hori R., Tanigawara Y., Saito Y., Hayashi Y., Aiba T., Okumura K., Kamiya A.

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

ISSN 0022-3549

The mean renal epithelial cell residence time, T̄(cell), 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 T̄(cell) 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 T̄(cell). p-Aminohippuric 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 cathether 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.

腎機能障害者におけるcefixime(CFIX)の体内動態

中野　博，世古　昭三，仁平　寛巳，枡知　果夫，児玉　光人，谷川原　祐介，神谷　晃，堀　了平

Chemotherapy 36 （ 5 ） 428 - 436 1988年

ISSN 0009-3165

The design of membrane-controlled transdermal therapeutic systems containing molsidomine

Yamada M., Tanigawara Y.

Chemical and Pharmaceutical Bulletin 35 （ 8 ） 3407 - 3412 1987年

ISSN 0009-2363

Mechanism of enhancement of percutaneous absorption of molsidomine by oleic acid

Yamada M., Uda Y., Tanigawara Y.

Chemical and Pharmaceutical Bulletin 35 （ 8 ） 3399 - 3406 1987年

ISSN 0009-2363

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