研究者詳細 - 大谷　壽一

論文 - 大谷　壽一

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塩酸ドネペジルの臨床における使用の実態　薬剤師に対するアンケート調査

児玉裕克, 大谷壽一, 澤田康文

医療薬学（(一社)日本医療薬学会） 30 （ 6 ） 413 - 419 2004年06月

ISSN 1346-342X

「インターネットを用いた薬剤師間情報交換・研修システム」を介して,塩酸ドネペジルの添付文書に規定されている用法・用量から逸脱した症例を確認した.中でも「初回から3mgあるいは5mg未満の量で1〜2週間後も継続されている」という,有効性が期待できない用量での処方が最も多く認められた.アンケート調査の結果および河野らの報告を考慮すると,3mg/日以下の投与量で有効で,かつ副作用が軽減される患者が存在する可能性は高いが,現段階では,医療用添付文書に定められた用法および用量を遵守する必要があり,規定外の投与は推奨できない.よって,臨床試験により,血中濃度と治療効果の関係を明らかにするとともに,低用量における治療効果を評価する必要性が示唆された

Tolbutamide Uptake Via pH- and Membrane-potential-dependent Transport Mechanism in Mouse Brain Capillary Endothelial Cell Line

Koyabu N., Takanaga H., Matsuo H., Ohtani H., Sawada Y., Naito M., Tsuruo T.

Drug Metabolism And Pharmacokinetics （Drug Metabolism And Pharmacokinetics） 19 （ 4 ） 270 - 279 2004年02月

ISSN 13474367

Summary: The purpose of this study was to investigate the transport mechanism of tolbutamide across the blood-brain barrier (BBB) using MBEC4 cells as an in vitro BBB model. Methods: The BBB transport of tolbutamide was studied by using a mouse brain capillary endothelial cell line, MBEC4, cultured on dishes with their luminal membrane facing the culture medium. Results: The uptake of [14Cltolbutamide by MBEC4 cells was dependent on temperature and energy. The uptake coefficient of [14C]tolbutamide increased markedly with decreasing pH of the external medium from neutral to acidic. Valinomycin and replacement of chloride with sulfate or gluconate significantly increased the initial uptake of [14C]tolbutamide, while replacement with nitrate significantly decreased it. The uptake was significantly reduced by a proton ionophore, FCCP, and an anion-exchange inhibitor, DIDS. The initial uptake of [14C]tolbutamide was saturable with Kt of 0.61 ± 0.03 mM (pH 7.4) and 1.76±0.19 mM (pH 6.5). At pH 6.5, the initial uptake of [14C]tolbutamide was significantly reduced by several sulfa drugs, salicylic acid, valproic acid and probenecid, and was competitively inhibited by sulfaphenazole (Ki = 3.47 ±0.50 mM) and valproic acid (Ki = 2.29 ±0.43 mM). Conclusion: These observations indicate the existence of a pH-and membrane-potential-dependent anion exchange and/or proton-cotransport system(s) for concentrative uptake of tolbutamide and sulfa drugs in MBEC4 cells. © 2004, The Japanese Society for the Study of Xenobiotics. All rights reserved.

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Decreased Phenobarbital Absorption with Charcoal Administration for Chronic Renal Failure

Tanaka C., Yagi H., Sakamoto M., Koyama Y., Ohmura T., Ohtani H., Sawada Y.

Annals of Pharmacotherapy （Annals of Pharmacotherapy） 38 （ 1 ） 73 - 76 2004年01月

ISSN 10600280

OBJECTIVE: To report a case of impaired absorption of orally administered phenobarbital associated with the concomitant administration of activated charcoal, and recovery of the absorption after administration of the 2 drugs was separated by a 1.5-hour interval. CASE SUMMARY: A 78-year-old woman, weighing 50 kg, who had undergone brain surgery was prescribed phenobarbital 120 mg/day for postoperative convulsions. Her serum phenobarbital concentration reached 24.8 μg/mL (therapeutically effective level 10-30). Thereafter, her renal function worsened, and activated charcoal 6 g/day was started. Four months after the start of activated charcoal, blood analysis revealed that the serum phenobarbital concentration was as low as 4.3 μg/mL. The phenobarbital dose was increased to 150 mg/day. Further evaluation revealed that activated charcoal and phenobarbital had been administered concomitantly. The dosage regimen was altered to separate the administration of the agents by at least 1. 5 hours. Subsequently, the patient's serum phenobarbital concentration increased to 11.9 μg/mL within 3 weeks. Her serum phenobarbital concentration was measured monthly thereafter and remained stable in the range of 14.8-18.6 μg/mL. DISCUSSION: Our patient's low serum phenobarbital concentration was considered likely to have been due to impaired gastrointestinal absorption of phenobarbital as a result of adsorption of phenobarbital on the activated charcoal. An objective causality assessment showed that the interaction was probable. CONCLUSIONS: Administration of activated charcoal and phenobarbital should be separated by an interval of at least 1.5 hours.

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Basal membrane localization of MRP1 in human placental trophoblast

Nagashige M., Ushigome F., Koyabu N., Hirata K., Kawabuchi M., Hirakawa T., Satoh S., Tsukimori K., Nakano H., Uchiumi T., Kuwano M., Ohtani H., Sawada Y.

Placenta （Placenta） 24 （ 10 ） 951 - 958 2003年11月

ISSN 01434004

The placental trophoblast is considered to act as a barrier between mother and fetus, mediating the exchange of various materials across the placenta. ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) and multidrug-resistance protein (MRP) are expressed in the placenta and function as efflux transport systems for xenobiotics. In the present study, we aimed to determine the localization of MRP1 in the human placenta in comparison with that of P-gp. Western blotting analysis with human placental membrane vesicles indicated that P-gp and MRP1 are localized on the brush-border membranes and basal membranes, respectively. Immunohistochemical analysis with human normal full-term placenta showed that anti-P-gp monoclonal antibody F4 stained the brush-border side of the trophoblast cells, whereas anti-MRP1 monoclonal antibody MRPr1 stained the basal side. These results confirm that P-gp and MRP1 are located on the brush-border membranes and basal membranes, respectively, of human full-term placental trophoblast. MRP1 was also detected on the abluminal side of blood vessels in the villi. Accordingly, MRP1 may play a role distinct from that of P-gp, which is considered to restrict the influx of xenobiotics into the fetus. © 2003 Elsevier Ltd. All rights reserved.

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In vivo delivery of glial cell-derived neurotrophic factor across the blood-brain barrier by gene transfer into brain capillary endothelial cells

Jiang C., Koyabu N., Yonemitsu Y., Shimazoe T., Watanabe S., Naito M., Tsuruo T., Ohtani H., Sawada Y.

Human Gene Therapy （Human Gene Therapy） 14 （ 12 ） 1181 - 1191 2003年08月

ISSN 10430342

The gene encoding mouse glial cell-derived neurotrophic factor (mGDNF gene) was transfected into brain capillary endothelial cells (BCECs) with the aim of delivering the gene product extensively into the brain parenchyma by making use of the secretory function of BCECs. First, we transfected mGDNF gene into cultured BCECs (MBEC4; mouse brain capillary endothelial cells) in vitro. The amount of mGDNF protein secreted from the transfected cells into the medium was 1500 to 3200 pg/mg of cell protein per day, being about sevenfold higher than that accumulated intracellularly. Furthermore, the basolateral-directed secretion of mGDNF protein from the transfected MBEC4 cells was fivefold higher than the apical-directed secretion. Next, the hemagglutination virus of Japan (HVJ)-liposomes encapsulating mGDNF gene were administered to rats in vivo via the internal carotid artery. The transfected rats showed a marked increase in the brain level of GDNF as assessed by means of enzyme-linked immunosorbent assay (ELISA) and Western blotting on day 3 after the administration, and the level remained significantly elevated for at least 12 days. Furthermore, immunohistochemical staining revealed an increase in GDNF immunoreactivity throughout the transfected forebrain. These results indicate that the gene was successfully transferred in vivo from HVJ-liposomes into BCECs, where it was expressed, and the gene product was secreted into the brain. Then, using this delivery method, we evaluated the protective effect for dopamine neuron against a retrograde 6-hydroxydopamine (6-OHDA) lesion, as assessed by behavioral and neurochemical indices.

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Betaxolol-induced deterioration of asthma and a pharmacodynamic analysis based on β-receptor occupancy

Miki A., Tanaka Y., Ohtani H., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics （International Journal of Clinical Pharmacology and Therapeutics） 41 （ 8 ） 358 - 364 2003年08月

ISSN 09461965

Objective: To report a case of deterioration of asthma associated with continuous use of oral betaxolol, a β1-selective β-blocking agent. We also analyzed the pharmacokinetics in this case by applying a receptor occupancy model. Case summary: A 68-year-old woman taking 5 mg of betaxolol for hypertension occasionally experienced asthmatic coughing after upper respiratory tract infection. Two years after the start of betaxolol, her asthma gradually worsened. Although pharmacotherapy for asthma was introduced, betaxotol was continued. Finally, she was admitted to hospital with bronchospasm. When she was discharged after 2 months, betaxolol was discontinued and losartan potassium (25 mg/d) was initiated instead for her hypertension. Since then, she has been free from bronchospasm. Method: We calculated the mean receptor occupancy (Φss) of the β1- and β2-receptors after the usual oral dose of betaxolol by using pharmacokinetic-pharmacodynamic parameters obtained from the literature. We estimated the decrease in the exercise pulse rate or the forced expiratory volume in 1 second (FEV1) by applying the Φss values to the model previously reported by us. Results: Betaxolol seems less likely than other β1-blocking agents to cause pulmonary adverse effects. However, the estimated decrease in FEV1 after oral administration of betaxolol (5 mg) was close to that after oral bisoprolol (5 mg), which has been reported to induce asthma. Conclusions: Oral betaxolol may induce bronchospasm, although betaxolol is considered to be highly cardioselective and seems less likely than other β1-selective blocking agents to cause pulmonary adverse effects. Betaxolol should be administered with caution to patients with asthma or chronic pulmonary disease.

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Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide

Hanada E., Ohtani H., Hirota M., Uemura N., Nakaya H., Kotaki H., Sato H., Yamada Y., Iga T.

Journal of Pharmacy and Pharmacology （Journal of Pharmacy and Pharmacology） 55 （ 7 ） 995 - 1002 2003年07月

ISSN 00223573

Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10-100 μM) and erythromycin (100 μM) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 ± 0.17 μM) and Ito (IC50 = 20.9 ± 0.13 μM) while erythromycin reduced IK (IC50 = 60.1 ± 0.29 μM) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.

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Pomelo-induced increase in the blood level of tacrolimus in a renal transplant patient

Egashira K., Fukuda E., Onga T., Yogi Y., Matsuya F., Koyabu N., Ohtani H., Sawada Y.

Transplantation （Transplantation） 75 （ 7 ） 1057 2003年04月

ISSN 00411337

Background. Tacrolimus, an immunosuppressive agent, is widely used in patients after transplantation to prevent allograft rejection. Because tacrolimus has a narrow therapeutic range, it is essential to carefully control the blood level. It has been demonstrated that tacrolimus is metabolized mainly by cytochrome P-450 (CYP) 3A4, and that tacrolimus is a substrate of P-glycoprotein. Methods. This article reports a case of considerable increase in the blood level of tacrolimus after the intake of pomelo in a renal transplant recipient. Results. Pomelo may increase the blood concentration of tacrolimus by inhibiting CYP 3A4, P-glycoprotein, or both. Conclusions. Patients taking drugs such as tacrolimus or cyclosporine, which have their kinetics affected by grapefruit juice, should avoid pomelo and other grapefruit-related citrus fruits.

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Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A

Tsujikawa K., Dan Y., Nogawa K., Sato H., Yamada Y., Murakami H., Ohtani H., Sawada Y., Iga T.

Biopharmaceutics and Drug Disposition （Biopharmaceutics and Drug Disposition） 24 （ 3 ） 105 - 114 2003年04月

ISSN 01422782

The distribution of domperidone (DOM), a peripheral dopamine D2 receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood-brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D2 antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D1, D2 and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D1, D2 and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D1 and D2 receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA. Copyright © 2003 John Wiley & Sons, Ltd.

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Kinetic analysis of P-glycoprotein-mediated transport by using normal human placental brush-border membrane vesicles

Ushigome F., Koyabu N., Satoh S., Tsukimori K., Nakano H., Nakamura T., Uchiumi T., Kuwano M., Ohtani H., Sawada Y.

Pharmaceutical Research （Pharmaceutical Research） 20 （ 1 ） 38 - 44 2003年01月

ISSN 07248741

Purpose. P-Glycoprotein (Pgp) plays an important role in drug disposition and excretion in various tissues such as the brain, intestine, and kidney. Moreover, we have demonstrated that Pgp is expressed on the brush-border membranes of trophoblast cells in the placenta and restricts drug transfer from the maternal circulation to the fetus. However, the transport kinetics of physiologically expressed Pgp has scarcely been investigated. Methods. In this study, we assessed the functional kinetics of transport mediated by Pgp that is physiologically expressed in normal tissue by using human placental brush-border membrane vesicles (BBMVs). Digoxin and vinblastine were used as typical substrates of Pgp. Results. The uptakes of [3H] digoxin and [3H] vinblastine into BBMVs were significantly increased in the presence of an ATP-regenerating system. The ATP-dependent uptakes of [3H]digoxin and [3H] vinblastine into BBMVs exhibited saturable kinetics. The Michaelis constants (Kt values) were 2.65 ± 1.80 μM and 21.9 ± 3.37 μM, respectively. In the presence of a Pgp inhibitor such as verapamil, cyclosporine A, or progesterone, the ATP-dependent uptakes of [3H]digoxin and [3H] vinblastine into BBMVs were significantly reduced. Anti-Pgp monoclonal antibody C219 completely inhibited the uptake of [3H] digoxin. Conclusions. The transport kinetics of [3H]digoxin and [3H]vinblastine by physiologically expressed Pgp were successfully evaluated by using BBMVs prepared from normal human placenta. The present method enabled us to evaluate the function of physiologically expressed Pgp and is superior to the use of cultured transfectants in terms of the yield of vesicles. The present method may also be applicable to investigating the influence of various factors such as the genotype of the MDR1 gene or various pathophysiologic states of neonates on the function of Pgp.

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Agranulocytosis possibly caused by ranitidine in a patient with renal failure

Takami N., Yamamoto Y., Matsuo H., Ohtani H., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics （International Journal of Clinical Pharmacology and Therapeutics） 40 （ 11 ） 520 - 523 2002年11月

ISSN 09461965

A 70-year-old Japanese woman with renal dysfunction under hemodialysis presented with vomiting and chill with fever. Over the previous 24 weeks she had been taking 75 mg of ranitidine after hemodialysis. Other medications taken were prednisolone, furosemide, α-calcidol, amlodipine and calcium carbonate. Before starting ranitidine, she had been treated with famotidine for about 2 years without complication. Hematological inspection on admission revealed agranulocytosis with WBC of 400/mm3. Ranitidine was discontinued and granulocyte colony-stimulating factor (G-CSF) was started. On Day 3, laboratory data showed slight improvement of cytopenia with WBC Of 1,000/mm3. On Day 6, her hemogram showed marked improvement with WBC of 11,700/mm3 and G-CSF was discontinued. She was discharged on Day 10. Several cases describing ranitidine-induced cytopenia are associated with the use of ranitidine at a dose of 150 mg/day or higher, and adverse reactions were found within 2 - 35 days after beginning ranitidine treatment. In the case described here, however, the adverse reaction occurred after a longer treatment period with ranitidine at a lower dose. In conclusion, ranitidine should be administered with great caution to patients with severe renal dysfunction.

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Nightmares and panic disorder associated with carvedilol overdose

Maebara C., Ohtani H., Sugahara H., Mine K., Kubo C., Sawada Y.

Annals of Pharmacotherapy （Annals of Pharmacotherapy） 36 （ 11 ） 1736 - 1740 2002年11月

ISSN 10600280

OBJECTIVE: To report a case of nightmares and sleep disorder associated with improper use of carvedilol, an α/β-blocker, and to model the time course of receptor occupancy in this patient. CASE SUMMARY: A 41-year-old man with panic disorder had been treated with alprazolam 1.2 mg/d (3 times daily), carvedilol 10 mg/d (once in the morning), and etizolam 0.5 mg (for anxiety attack). Although the physical and psychological symptoms gradually improved, he reported nightmares and panic attacks. An interview revealed that he had been taking carvedilol 5 mg twice a day after lunch and dinner on his own initiative, in addition to the prescribed dosage. The patient was asked to take carvedilol 10 mg only after breakfast, as had been advised. Consequently, the sleep disorder and nightmares disappeared. METHODS: We calculated the time courses of β2-adrenoceptor binding occupancy in the central nervous system after oral administration of carvedilol with the ordinary and improper regimens by using pharmacokinetic/pharmacodynamic parameters obtained from the literature. RESULTS: Compared with the ordinary dose of carvedilol 10 mg once a day, the improper regimen (10 mg after breakfast followed by 5 mg after lunch and dinner) increases the β2-adrenoceptor binding occupancy at night (2300) to as high as the mean β2-adrenoceptor binding occupancy after an ordinary dose of propranolol. CONCLUSIONS: The sleep disorder and nightmares experienced by this patient had been induced by elevation of central β2-adrenoceptor binding occupancy at night as the result of improper use of carvedilol.

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非循環系薬物による致死性心電学的副作用の定量的予測法の確立

大谷壽一

上原記念生命科学財団研究報告集（(公財)上原記念生命科学財団） 16 30 - 32 2002年11月

薬物による催不整脈作用をin vitroの実験から定量的に予測するために,動物実験におけるin vivo-in vitro相関の解析と,ヒトカリウムチャンネル発現系におけるカリウム電流阻害作用と臨床的報告に基づく副作用リスクとの解析を試みた.モルモットを用い,in vivo実験系として心電図の薬物動態・動力学的解析を,in vitro実験系としては摘出心臓還流標本における心電図測定を行い,両者の関係を解析した.in vivo実験ではキニジン(30mg/kg/h),ソタロール(5mg/kg/h)のいずれによっても心電図QTc間隔は最大30-40msec程度延長した.in vitro実験でもQTcはいずれの薬剤でも延長し,灌流液濃度とQTc延長との関係は直線関係が認められた.いずれの薬剤でもin vivoではin vitroよりもQTc延長の強度が強いことが明らかとなった.従って,in vitro実験結果をin vivoに外挿する場合には,両者の濃度的乖離を十分に考慮する必要があると考えられた

Functional characterization of mouse cation transporter mOCT2 compared with mOCT1

Kakehi M., Koyabu N., Nakamura T., Uchiumi T., Kuwano M., Ohtani H., Sawada Y.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications） 296 （ 3 ） 644 - 650 2002年10月

ISSN 0006291X

We characterized the function of mouse organic cation transporter OCT2 (TC 2.A.19.1.5) in comparison with that of OCT1 (TC 2.A.19.1.1). Uptake of [3H]1-methyl-4-phenylpyridinium ([3H]MPP+) by Xenopus laevis oocytes injected with mOCT1 (Slc22a1) or mOCT2 (Slc22a2) cRNA was attenuated by an increase of extracellular K+ concentration and under acidic extracellular conditions. The uptakes of [3H]MPP+ via mOCT1 and mOCT2 were saturable, with similar Michaelis constants (Kt) of 10 and 24 μM, respectively. mOCT2 also mediated the uptake of [14C]tetraethylammonium with a Kt value of 36 μM, which is similar to that of mOCT1. Quinine, tetraethylammonium, cimetidine, procainamide, choline, and N′-methylnicotinamide inhibited the uptake of [3H]MPP+ via mOCT1, as well as via mOCT2, and the inhibitory potencies for mOCT1 were comparable to but slightly higher than those for mOCT2. Thus, although the transport properties of mOCT2 are similar to those of mOCT1 in respect to the membrane-potential dependency, pH-sensitivity, and affinities for MPP+ and tetraethylammonium, several organic cations had weaker inhibitory effects on [3H]MPP+ uptake by mOCT2 than by mOCT1. © 2002 Elsevier Science (USA). All rights reserved.

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Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1

Okamura A., Emoto A., Koyabu N., Ohtani H., Sawada Y.

British Journal of Pharmacology （British Journal of Pharmacology） 137 （ 3 ） 391 - 399 2002年10月

ISSN 00071188

1 Nateglinide, a novel oral hypoglycemic agent, rapidly reaches the maximum serum concentration after oral administration, suggesting that it is rapidly absorbed in the gastrointestinal tract. The aim of this work is to clarify the intestinal absorption mechanism of nateglinide by means of in vitro studies. 2 We examined the transcellular transport and the apical uptake of [ 14C]nateglinide in a human colon carcinoma cell line (Caco-2). We also examined whether nateglinide is transported via monocarboxylate transport-1 (MCT1) by means of an uptake study using MCT1-expressing Xenopus laevis oocytes. 3 In Caco-2 cells, the transcellular transport of [ 14C]nateglinide from the apical to basolateral side was greater than that in the opposite direction. The uptake of [ 14C]nateglinide from the apical side was concentration-dependent, H +-dependent, and Na +-independent. Kinetic analysis revealed that the Kt and Jmax values of the initial uptake rate of [ 14C]nateglinide were 448 μM and 43.2 nmol mg protein -1 5 min -1, respectively. Various monocarboxylates, including salicylic acid and valproic acid, and glibenclamide significantly inhibited the uptake of [ 14C]nateglinide. 4 The uptake study using MCT1-expressing oocytes showed that nateglinide inhibits the MCT1-mediated uptake of [ 14C]L-lactic acid, though nateglinide itself is not transported by MCT1. 5 Taken together, these results suggest that the uptake of nateglinide from the apical membranes of Caco-2 cells is, at least in part, mediated by a proton-dependent transport system(s) distinct from MCT1.

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Characteristics of L-lactic acid transport in basal membrane vesicles of human placental syncytiotrophoblast

Inuyama M., Ushigome F., Emoto A., Koyabu N., Satoh S., Tsukimori K., Nakano H., Ohtani H., Sawada Y.

American Journal of Physiology - Cell Physiology （American Journal of Physiology - Cell Physiology） 283 （ 3 52-3 ） C822 - 30 2002年09月

ISSN 03636143

The characteristics of L-lactic acid transport across the trophoblast basal membrane were investigated and compared with those across the brush-border membrane by using membrane vesicles isolated from human placenta. The uptake of L-[14C]lactic acid into basal membrane vesicles was Na+ independent, and an uphill transport was observed in the presence of a pH gradient ([H+]out > [H+]in). L-[14C]lactic acid uptake exhibited saturation kinetics with a Km value of 5.89 ± 0.68 mM in the presence of a pH gradient. p-Chloromercuribenzenesulfonate and α-cyano-4-hydroxycinnamate inhibited the initial uptake, whereas phloretin or 4,4′-diisothiocyanostilbene-2,2′-disulfonate did not. Mono- and dicarboxylic acids suppressed the initial uptake. In conclusion, L-lactic acid transport in the basal membrane is H+ dependent and Na+ independent, as is also the case for the brush-border membrane transport, and its characteristics resemble those of monocarboxylic acid transporters. However, there were several differences in the effects of inhibitors between basal and brush-border membrane vesicles, suggesting that the transporter(s) involved in L-lactic acid transport in the basal membrane of placental trophoblast may differ from those in the brush-border membrane.

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Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT<inf>3</inf> receptor antagonist, across the blood-brain barrier

Yamamoto C., Murakami H., Koyabu N., Takanaga H., Matsuo H., Uchiumi T., Kuwano M., Naito M., Tsuruo T., Ohtani H., Sawada Y.

Journal of Pharmacy and Pharmacology （Journal of Pharmacy and Pharmacology） 54 （ 8 ） 1055 - 1063 2002年08月

ISSN 00223573

In-situ rat and mouse brain perfusion data indicated that the brain distribution of ramosetron (R-ramosetron), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was extremely low compared with that expected from its lipophilicity. We hypothesized the involvement of an efflux system(s) and investigated the contribution of P-glycoprotein to efflux transport of ramosetron across the blood-brain barrier by means of an in-vitro uptake study in cell lines that over-express P-glycoprotein. We examined the contribution of mdr1a, mdr1b and MDR1 P-glycoprotein by using LV500 cells, MBEC4 cells and LL-GA5-COL300 cells, which over-express mdr1a P-glycoprotein, mdr1b P-glycoprotein and MDR1 P-glycoprotein, respectively. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly lower than that by the respective parental cells. Next, we studied the effects of P-glycoprotein inhibitors, verapamil and ciclosporin, on uptake of [14C] ramosetron by these cell lines. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly increased in the presence of verapamil or ciclosporin, while verapamil did not affect the uptake of [14C]ramosetron by MBEC4 cells. These results indicate that the efflux of [14C]ramosetron is partly mediated by mdr1a P-glycoprotein, but not by mdr1b P-glycoprotein, and that there is a difference in substrate specificity between mdr1a P-glycoprotein and mdr1b P-glycoprotein. Further, [14C]ramosetron was confirmed to be effluxed by human MDR1 P-glycoprotein. We conclude that the limited distribution of ramosetron to the brain is due, at least in part, to efflux mediated by the P-glycoprotein at the blood-brain barrier.

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Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein

Kurata Y., Ieiri I., Kimura M., Morita T., Irie S., Urae A., Ohdo S., Ohtani H., Sawada Y., Higuchi S., Otsubo K.

Clinical Pharmacology and Therapeutics （Clinical Pharmacology and Therapeutics） 72 （ 2 ） 209 - 219 2002年08月

ISSN 00099236

Objective: Our objective was to quantitate the contribution of the genetic polymorphism of the human MDR1 gene to the bioavailability and interaction profiles of digoxin, a substrate of P-glycoprotein. Methods: The pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups (n = 5 each) on the basis of genotyping for the MDR1 gene, in a 4-dose study after single doses of digoxin alone (0.5 mg orally and intravenously) and coadministered with clarithromycin (400 mg orally for 8 days). The dose of digoxin was reduced during the clarithromycin phase (0.25 mg orally and intravenously). Results: The bioavailability of digoxin in G/G2677C/C3435, G/T2677C/T3435, and T/T2677T/T3435 subjects were 67.6% ± 4.3%, 80.9% ± 8.9%, and 87.1% ± 8.4%, respectively, and the difference between G/G2677C/C3435 and T/T2677T/T3435 subjects was statistically significant (P < .05). The MDR1 variants were also associated with differences in disposition kinetics of digoxin, with the renal clearance being almost 32% lower in T/T2677T/T3435 subjects (1.9 ± 0.1 mL/min per kilogram) than G/G2677C/C3435 subjects (2.8 ± 0.3 mL/min per kilogram), and G/T2677C/T3435 subjects having an intermediate value (2.1 ± 0.6 mL/min per kilogram). Coadministration of clarithromycin did not consistently affect digoxin clearance or renal clearance. However, a significant increase in digoxin bioavailability was observed in G/G2677C/C3435 subjects (67.6% ± 4.3% versus 85.4% ± 6.1%; P < .05) but not in the other 2 genotype groups. Conclusion: The allelic variants in the human MDR1 gene are likely to be associated with altered absorption and/or disposition profiles of digoxin and P-glycoprotein-mediated drug interaction.

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Transluminal gene transfer into brain capillary endothelial cells in vivo with HVJ-liposomes

Jiang C., Matsuo H., Koyabu N., Ohtani H., Fujimoto H., Yonemitsu Y., Kaneda Y., Naito M., Tsuruo T., Sawada Y.

Journal of Drug Targeting （Journal of Drug Targeting） 10 （ 4 ） 345 - 352 2002年07月

ISSN 1061186X

Bioactive proteins or peptides cannot be effectively delivered into brain capillary endothelial cells (BCECs) or brain parenchyma. In this study, we selectively transferred Escherichia coli β-galactosidase gene (β-gal) as a model gene into BCECs by using the hemagglutination virus of Japan (HVJ)-liposomes. HVJ-liposomes encapsulating a β-gal plasmid were used to transfect MBEC4 cells in vitro, and were administrated via the internal carotid artery to rat in vivo. Success of the procedure was confirmed by the detection of 116 kDa β-gal protein in transfected MBEC4 cells and in brain capillaries isolated from transfected rats, by Western blot analysis and histological staining. The enzymatic activities of β-galactosidase were 5- to 10-fold and 20-fold higher than when β-gal-containing liposomes without fusogenic activity (uncoated liposomes) or plasmid alone were employed in vitro and in vivo, respectively. Thus, HVJ-liposomes were demonstrated to be a useful vector to transfer a foreign gene into the brain capillary endothelium in vivo via the transluminal route.

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Distribution of domperidone into the rat brain is increased by brain ischaemia or treatment with the P-glycoprotein inhibitor verapamil

Dan Y., Murakami H., Koyabu N., Ohtani H., Sawada Y.

Journal of Pharmacy and Pharmacology （Journal of Pharmacy and Pharmacology） 54 （ 5 ） 729 - 733 2002年05月

ISSN 00223573

Domperidone (DOM), a peripheral dopamine D2 receptor antagonist, is a substrate of P-glycoprotein (P-gp). Therefore, the transport of DOM into the brain may be restricted by P-gp function at the blood-brain barrier, and when the function of P-gp is impaired by ATP depletion under conditions of brain ischaemia (e.g. cerebral thrombosis), side-effects may be induced as a result of increased distribution of DOM into the brain. In this study, we investigated the effects of brain ischaemia and verapamil, a P-gp inhibitor, on the permeability coefficient-surface area product (PS values) of DOM across the blood-brain barrier by using an in-situ rat brain perfusion technique. The PS values of DOM were increased 3.4- and 3.6-fold after brain ischaemia for 10 and 20 min, respectively. Furthermore, co-administration of verapamil significantly increased the PS values of DOM by 42.6- and 43.3-fold in the normal and ischaemia groups, respectively. Brain vascular volume was not affected by ischaemia or verapamil. These results show that the transport of DOM into the brain is restricted by P-gp and that the brain distribution of DOM can be increased by cerebral ischaemia or co-administration of a P-gp inhibitor.

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