Details of a Researcher - Ohtani, Hisakazu

Papers - Ohtani, Hisakazu

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Functional characterization of adenosine transport across the BBB in mice.

Murakami H, Ohkura A, Takanaga H, Matsuo H, Koyabu N, Naito M, Tsuruo T, Ohtani H, Sawada Y*.

International Journal of Pharmaceutics (International Journal of Pharmaceutics) 290(1-2) ( 1-2 ) 37-44 - 44 2005.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 03785173

We investigated transport characteristics of adenosine across the blood-brain barrier (BBB) in mice. Uptake clearance across the BBB was measured by using an in situ mouse brain perfusion technique and cultured mouse brain capillary endothelial cell line (MBEC4 cells). Nucleoside transporter was cloned by RT-PCR and expressed on Xenopus laevis oocyte. Both in situ and in vitro studies revealed that the adenosine uptake is concentration-dependent, Na +-independent and S-(p-nitrobenzyl)-6-thioinosine (NBMPR)-sensitive. The Kt values of in situ and in vitro studies were 31.7 ± 13.8 μM and 11.9 ± 2.84 μM, respectively. A good correlation was found for the inhibitory effects of nucleoside analogs to adenosine uptake between in situ and in vitro studies. RT-PCR revealed the expression of RNA of mouse equilibrative nucleoside transporter (mENT1) in mouse brain capillary and MBEC4 cells. In mENT1 expressed on X. laevis oocyte, Kt value of adenosine transport was 6.9 ± 2.7 μM (and comparable to those in situ and in vitro studies). In conclusion, we characterized the adenosine transport across the BBB in mice by using in situ brain perfusion technique and MBEC4 cells and found that these transports share common characteristics with mENT1-mediated transport. Transport of adenosine across the BBB in mice may be attributable to mENT1. © 2004 Elsevier B.V. All rights reserved.

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Interactions between clarithromycin and digoxin in patients with end-stage renal disease.

Hirata S, Izumi S, Furukubo T, Ota M, Fujita M, Yamakawa T, Hasegawa I, Ohtani H, Sawada Y*.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 43(1) ( 1 ) 30-36 - 36 2005.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 09461965

Objective: To report a significant increase in the serum levels of digoxin associated with the use of clarithromycin in six patients undergoing renal replacement therapy. Case summary: All six patients were males with end-stage renal disease and in need of renal replacement therapy. Four patients were anuric. The mean age was 78.8 ± 5.8 (66-83) years. All patients except one, who was treated by hemofiltration, were treated by hemodialysis. All patients except one, who had been treated with metildigoxin (0.35 mg/week), were also taking digoxin (0.375 mg/week). Clarithromycin was administered at a dose of 200 - 400 mg/day for the treatment of bronchitis in all patients. The concomitant administration of clarithromycin increased serum digoxin levels from 1.8 - 4.0-fold in all cases. In two of six cases, a high probability of digoxin intoxication and suspicion of digoxin intoxication was evident. In three of six cases, serum digoxin levels increased within 12 days after the co-administration of clarithromycin, while in the other three cases, serum digoxin levels were increased 53 - 190 days after the administration of clarithromycin. Conclusion: The simultaneous administration of clarithromycin caused an increase in digoxin levels in six patients undergoing renal replacement therapy. The increase in the serum digoxin can be attributed to the inhibition of P-glycoprotein in the intestine and/or bile capillary rather than the kidney by clarithromycin since renal function was dramatically impaired, and four of the patients were anuric. The issue of why serum digoxin levels were increased so late in three patients undergoing renal replacement is unclear. However, this interaction seemed to be clinically significant even in ESRD patients, whose renal function was highly impaired. The simultaneous use of digoxin and clarithromycin sbould be avoided even in patients undergoing renal replacement therapy whose renal function is impaired, since digoxin levels may increase unexpectedly. ©2005 Dustri-Verlag Dr. K. Feistle.

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Association between neuroleptic drug-induced extrapyramidal symptoms and dopamine D<inf>2</inf>-receptor polymorphisms in Japanese schizophrenic patients

Nakazono Y., Abe H., Murakami H., Koyabu N., Isaka Y., Nemoto Y., Murata S., Tsutsumi Y., Ohtani H., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 43 ( 4 ) 163 - 171 2005

ISSN 09461965

The aim of the present study is to examine the relationship between dopamine D2-receptor gene (DRD2) polymorphisms (Taq1A, Taq1B, -141C Ins/Del) and the risk of extrapyramidal adverse effects (EPS), assessed according to the Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS), or the maintenance dose of antipsychotics in schizophrenic patients. The DIEPSS score was significantly higher in patients bearing the -141C Del allele than in those without it. Taq1A and Taq1B restriction fragment length polymorphisms (RFLPS) did not significantly affect the DIEPSS score. On the other hand, maintenance doses of neuroleptics and antiparkinsonian drugs were significantly higher in patients with the B1 allele of Taq1B RFLP than in those without it, while the Taq1A RFLP and -141C Ins/Del polymorphisms were not significantly related to the maintenance doses. In conclusion, the risk of EPS may be increased in patients with the -141C Del allele of the DRD2 gene. In these patients, antipsychotics should be administered with caution. ©2005 Dustri-Verlag Dr. K. Feistle.

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Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux

Honda Y., Ushigome F., Koyabu N., Morimoto S., Shoyama Y., Uchiumi T., Kuwano M., Ohtani H., Sawada Y.

British Journal of Pharmacology (British Journal of Pharmacology) 143 ( 7 ) 856 - 864 2004.12

ISSN 00071188

1 We investigated the effects of grapefruit juice (GFJ) and orange juice (OJ) on drug transport by MDR1 P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), which are efflux transporters expressed in human small intestine. 2 We examined the transcellular transport and uptake of [ 3H]vinblastine (VBL) and [ 14C]saquinavir in a human colon carcinoma cell line (Caco-2) and in porcine kidney epithelial cell lines transfected with human MDR1 cDNA and human MRP2 cDNA, LLC-GA5-COL150, and LLC-MRP2, respectively. 3 In Caco-2 cells, the basal-to-apical transports of [ 3H]VBL and [ 14C]saquinavir were greater than those in the opposite direction. The ratio of basal-to-apical transport to apical-to-basal transport of [ 3H]VBL and [ 14C]saquinavir by Caco-2 cells was reduced in the presence of MK571 (MRPs inhibitor), verapamil (P-gp inhibitor), cyclosporin A (inhibitor of both), 50% ethyl acetate extracts of GFJ and OJ, or their components (6′,7′-dihydroxybergamottin, bergamottin, tangeretin, hepatomethoxyflavone, and nobiletin). 4 Studies of transport and uptake of [ 3H]VBL and [ 14C]saquinavir with MDR1 and MRP2 transfectants showed that VBL and saquinavir are transported by both P-gp and MRP2. GFJ and OJ components inhibited the transport by MRP2 as well as P-gp. However, their inhibitory potencies for P-gp or MRP2 were substrate-dependent. 5 The present study has revealed that GFJ and OJ interact with not only P-gp but also MRP2, both of which are expressed at apical membranes and limit the apical-to-basal transport of VBL and saquinavir in Caco-2 cells.

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Treatment of gastric hemorrhage by pulverized omeprazole and antacid - Concomitant administration via a nasogastric tube

Yamaguchi T., Mukai S., Kinoshita E., Ohtani H., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 42 ( 11 ) 594 - 596 2004.11

ISSN 09461965

Gastroesophageal reflux (GER) is a common episode in pediatric patients with severe motor and intellectual disabilities (SMID) and occasionally leads to a severe clinical state accompanied with nausea, hematemesis, melena, wheezing, pneumonia, anemia and/or failure to thrive. We report here a case of a 14-year-old male with Lennox syndrome who had been treated with a histamine H2 blocker intravenously or via a nasogastric tube for repeated gastric hemorrhage due to severe GER. Since his gastric hemorrhage became resistant to the H2 blocker, we decided to replace it with a proton pump inhibitor (PPI). Although lansoprazole can be decapsulated for administration via a nasogastric tube, it tends to block fine tubes. The acid-sensitive drug omeprazole, another oral PPI, is commercially available as enteric-coated tablets. Therefore, we pulverized the tablets and administered omeprazole, mixed with a small amount of antacid, via a nasogastric tube. The patient's gastric hemorrhage was dramatically improved. Thus, administration of pulverized omeprazole concomitantly with antacid via a fine nasogastric tube may provide a novel approach for the treatment of chronic GER in pediatric patients with SMID. © 2004 Dustri-Verlag Dr. K. Feistle.

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Inhibitory effects of pomelo on the metabolism of tacrolimus and the activities of CYP3A4 and P-glycoprotein

Egashira K., Ohtani H., Itoh S., Koyabu N., Tsujimoto M., Murakami H., Sawada Y.

Drug Metabolism and Disposition (Drug Metabolism and Disposition) 32 ( 8 ) 828 - 833 2004.08

ISSN 00909556

We recently reported a case of increase in the blood level of tacrolimus following intake of pomelo in a renal transplant recipient. To clarify the mechanism of this increase in the blood level of tacrolimus, we investigated the effect of pomelo juice extract on the activities of CYP3A4 and P-glycoprotein, in comparison with that of extract of grapefruit juice (GFJ). The 10% ethyl acetate extracts of the juice of three pomelos of different origins (Banpeiyu, pomelo I; Hirado Buntan, pomelo II; and Tosa Buntan, pomelo III) and GFJ significantly inhibited 6β-hydroxylation of testosterone in human liver microsomes by 76.4, 67.2, 37.5, and 83.9%, respectively. The extract of pomelo I was as potent as that of GFJ. The metabolism of tacrolimus itself was also inhibited by the extract of pomelo I, as well as that of GFJ. Furthermore, the inhibition of both 6β-hydroxylation of testosterone and metabolism of tacrolimus by pomelo I and GFJ was preincubation time-dependent. On the other hand, the extract of pomelo I had little effect on the transcellular transport of tacrolimus or [3H]digoxin across a monolayer of LLC-GA5-COL150 cells (a porcine kidney epithelial cell line, LLC-PK1, transfected with human MDR1 cDNA and over-expressing human P-glycoprotein). In conclusion, pomelo constituents inhibit the activity of CYP3A4 and may thereby produce an increase in the blood level of tacrolimus.

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Various dosing weights and correction to serum digoxin assays in hemodialysis patients

Hirata S., Uenishi K., Izumi S., Furukubo T., Ota M., Fujita M., Yamakawa T., Ohtani H., Sawada Y.

Journal of Pharmacy Technology (Journal of Pharmacy Technology) 20 ( 4 ) 221 - 225 2004.07

ISSN 87551225

Background: Digoxin is distributed in skeletal muscles in high concentrations. The most reliable parameter to measure the distribution of digoxin in patients undergoing hemodialysis is not known. Objective: To estimate which distribution parameter-estimated lean body mass (E-LBM) calculated by subtracting the fat mass from the dry weight, lean body mass, dry weight, and ideal body weight - is the most reliable predictor for assessing the accuracy of a digoxin dosing regimen in patients undergoing hemodialysis. Methods: A retrospective study was conducted to evaluate 21 patients undergoing hemodialysis who were administered digoxin. The patients were divided into 2 groups: digoxin 0.125 mg administered twice a week (low-dose group) or 3 times per week (high-dose group). The differences between E-LBM, lean body mass, dry weight, and ideal body weight for the low- and high-dose groups were determined. The relationships between serum digoxin concentrations and the weekly digoxin dose per E-LBM, lean body mass, dry weight, and ideal body weight were also determined. Results: E-LBM, lean body mass, dry weight, and ideal body weight in the high-dose group were significantly larger than those in the low-dose group (p = 0.021, 0.015, 0.024, and 0.0029, respectively), although no significant difference in serum digoxin concentrations was evident. Significant correlation was found between serum digoxin concentrations and the weekly digoxin dosage per E-LBM, dry weight, lean body mass, and ideal body weight (r = 0.746, p < 0.0001; r = 0.638, p = 0.0014; r = 0.645, p < 0.0011; r = 0.553, p = 0.0083, respectively). Conclusions: E-LBM appears to reflect the best parameter for predicting serum digoxin concentrations. The use of the dry weight parameter could be generally useful for adjusting the dosage of digoxin in patients undergoing hemodialysis.

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Effect of hematocrit on pharmacokinetics of tacrolimus in adult living donor liver transplant recipients

Minematsu T., Sugiyama E., Kusama M., Hori S., Yamada Y., Ohtani H., Sawada Y., Sato H., Takayama T., Sugawara Y., Makuuchi M., Iga T.

Transplantation Proceedings (Transplantation Proceedings) 36 ( 5 ) 1506 - 1511 2004.06

ISSN 00411345

Objective Plasma drug concentrations are generally considered to reflect efficacy and pharmacokinetics more directly than those in whole blood. However, whole blood has been selected as the matrix to monitor concentrations of tacrolimus (FK506), because it is difficult to accurately measure plasma FK506 concentrations. Because FK506 highly and saturably binds in blood cells, a change in hematocrit value (Hct) may affect FK506 pharmacokinetics. Therefore, we investigated effects of Hct on FK506 pharmacokinetics. Methods First, we analyzed data on FK506 distribution among human blood cells in vitro. Briefly, we employed an equation, which describes saturable binding of FK506 to blood cells, and simulated plasma FK506 concentrations and clearances using the above equation with respect to a variable Hct. Subsequently, we retrospectively analyzed dosages and whole blood FK506 concentrations to predict plasma FK506 concentrations in living donor transplant recipients. Results In the simulation study, the Hct changed plasma FK506 concentrations and clearances based in whole blood. In living donor liver transplant recipients, whole blood FK506 concentrations were maintained within a therapeutic range, while the Hct varied after transplantation. The correlation of Hct with the ratio of dose/trough concentrations of FK506 (D/C) in plasma (D/Cp) (R = -0.23, n = 343) was weaker than that for D/C in whole blood (D/CWB) (R = -0.53, n = 343). Conclusion Hct may be an important factor affecting the pharmacokinetics of FK506 in living donor liver transplantation recipients. It may be necessary to take Hct into consideration in the FK506 dosing regimen, especially when the Hct is low.

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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 2004.06

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 2004.02

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 2004.01

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 2003.11

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 2003.08

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 2003.08

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 2003.07

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 2003.04

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 2003.04

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 2003.01

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 2002.11

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 2002.11

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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