研究者詳細 - 大谷　壽一

論文 - 大谷　壽一

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Polymorphisms and linkage disequilibrium of the OATP8 (OATP1B3) gene in Japanese subjects.

Tsujimoto M., Hirata S., Dan Y., Ohtani H., Sawada Y.

Drug metabolism and pharmacokinetics （Drug metabolism and pharmacokinetics） 21(2) （ 2 ） 165-169 - 169 2006年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

OATP8, a member of the organic anion-transporting polypeptide family, is expressed on the sinusoidal membrane of hepatocytes, and transports endogenous organic anions, such as 17beta-glucuronosyl estradiol, and xenobiotic substances, such as digoxin. The objective of this study is to search for polymorphisms of the OATP8 gene and to assess the allele frequency of the polymorphisms in the Japanese population. Analysis of the OATP8 gene in 79 subjects revealed complete linkage of two deletion polymorphisms in the 5' regulatory region, deletion from position -28 to -11 and deletion from position -7 to -4, with an allele frequency of 0.196 for the deletion allele. The polymorphisms T334G (Ser112Ala) and G699A (Met233Ile) were also shown to be in complete linkage disequilibrium, with an allele frequency of 0.728 for the variant (112Ala/233Ile) allele. Interestingly, linkage disequilibrium was identified between the ins/del polymorphism and SNPs at 112 and 233. The predicted major haplotype was the insert-variant type with a haplotype frequency of 0.60.

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テガフール,ギメラシル,オテラシルカリウム3剤配合抗癌剤(ティーエスワン)の適正使用の実態調査とWeb e-learningシステムの構築

辻野靖彦, 佐田宏子, 杉山清子, 友永雄二, 三木晶子, 堀里子, 大谷壽一, 澤田康文

医薬品情報学（(一社)日本医薬品情報学会） 7 （ 4 ） 293 - 299 2006年02月

ISSN 1345-1464

薬剤師によるティーエスワンに関する疑義照会の実態調査を行った.ティーエスワンの処方箋を応需した薬剤師において禁忌や他のフッ化ピリミジンからの切り替え時の注意などに理解がなく疑義照会に至らない処方箋チェックがあり,薬剤師への的確な医薬品情報提供の必要性が示された.ティーエスワンの処方を応需し,より多くの薬剤師に医薬品情報を効率よく提供する方法として,より実践的に処方箋応需業務を支援することを目的に,インターネットを介した薬剤師を対象とするWeb e-learningシステム(EL)を構築し評価を加えた.ELを使用した薬剤師のほとんどが参考になったと回答しており,ELは医薬品情報を提供するうえで受講者の満足度を得られる有用なシステムであることが証明でき,時間的自由度,学習効果,受講者の満足度とも良好であった

Receptor Occupancy-based Analysis of the Contributions of Various Receptors to Antipsychotics-induced Weight Gain and Diabetes Mellitus

Matsui-Sakata A., Ohtani H., Sawada Y.

Drug Metabolism And Pharmacokinetics （Drug Metabolism And Pharmacokinetics） 20(5) （ 5 ） 368-378 - 378 2005年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

Summary: Objective: Among various adverse reactions of atypical antipsychotics, weight gain and impaired glucose tolerance are clinically significant. The aim of this study is to analyze quantitatively the contributions of various receptors to these antipsychotics-induced adverse reactions based on the receptor occupancy theory. Methods: Two indices of antipsychotics-induced weight gain (the values estimated by a metaanalysis and the observed values in clinical trials) and the morbidity rate of type 2 diabetes mellitus during treatment with antipsychotics were taken from the literature. We calculated the estimated mean receptor occupancies of α1adrenergic, α2adrenergic, dopamine D2, histamine H1, muscarinic acetylcholine (mACh), serotonin 5-HT1A, 5-HT2Aand 5-HT2Creceptors by antipsychotics by using the pharmacokinetic parameters and receptor dissociation constants, and analyzed the correlation between the occupancies and the extent of adverse reactions as assessed using the aforementioned indices. Results: There were statistically significant correlations between the estimated occupancies of H1and mACh receptors and antipsychotics-induced weight gain estimated by metaanalysis (rs= 0.81 and rs= 0.83, respectively, p<0.01). There were also statistically significant correlations between these receptor occupancies and observed weight gain in clinical trials (rs= 0.66 in each case, p<0.01). The morbidity rate of type 2 diabetes mellitus was highly correlated with H1, mACh, and 5-HT2Creceptor occupancies (rs= 0.90 in each case, p<0.05). However, H1receptor occupancy was also highly correlated with mACh receptor occupancy among antipsychotics, so that only one of them may be critically associated with the adverse reactions. Considering that these adverse reactions have not been reported for drugs with mACh receptor antagonistic action, other than antipsychotics, the H1receptor may contribute predominantly to the antipsychotics-induced weight gain and diabetes mellitus. Discussion/Conclusion: Model analysis based on receptor occupancy indicates that H1receptor blockade is the primary cause of antipsychotics-induced weight gain and diabetes mellitus. © 2005, The Japanese Society for the Study of Xenobiotics. All rights reserved.

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Functional characterization of human monocarboxylate transporter 6 (SLC16A5)

Murakami Y., Kohyama N., Kobayashi Y., Ohbayashi M., Ohtani H., Sawada Y., Yamamoto T.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 33(12) （ 12 ） 1845-1851 - 1851 2005年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

Human monocarboxylate transporter 6 (MCT6) has recently been isolated, and its tissue distribution has been established at the mRNA level, but its functional properties remain unknown. The aim of this study is to investigate the transport properties of MCT6. When expressed in Xenopus laevis oocytes, MCT6 transported [3H]bumetanide in a pH- and membrane potential-sensitive but not proton gradient-dependent manner, with the Kt value of 84 μM. Furthermore, MCT6 transported various drugs such as probenecid and nateglinide. Neither [14C]L-lactic acid nor [3H]L- tryptophan, typical substrates of other MCT isoforms, was transported by MCT6. Four loop diuretics, i.e., furosemide, piretanide, azosemide, and torasemide, thiazides, probenecid, glibenclamide, and nateglinide inhibited the MCT6-mediated uptake of [3H]bumetanide. In contrast, short-chain carboxylic acids, such as L-lactic acid and succinic acid did not inhibit the MCT6-mediated uptake of bumetanide. These results suggest that the substrate specificity of MCT6 is distinct from those of other MCTs. Bumetanide would be a good tool for investigating the functional properties of MCT6. It is probable that MCT6 is involved in the disposition of various drugs, including bumetanide. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Inhibitory effects of various beverages on ritodrine sulfation by recombinant human sulfotransferase isoforms SULT1A1 and SULT1A3

Nishimuta H., Tsujimoto M., Ogura K., Hiratsuka A., Ohtani H., Sawada Y.

Pharmaceutical Research （Pharmaceutical Research） 22(8) （ 8 ） 1406-1410 - 1410 2005年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07248741

Purpose. Ritodrine is known to undergo extensive presystemic sulfation in the intestinal mucosa, and its bioavailability is as low as 30%. Accordingly, inhibition of intestinal sulfation may lead to an increase in the bioavailability of ritodrine. In this study, we aimed to investigate the activities of ritodrine sulfation by SULT1A1, which is expressed predominantly in the liver, and SULT1A3, which is expressed predominantly in the intestine, as well as the inhibitory effects of beverages on their activities. Methods. We investigated ritodrine sulfation by using recombinant human sulfotransferase (SULT) 1A1 and SULT1A3 in an in vitro study. Next, we investigated the inhibitory effects of grapefruit juice, orange juice, green tea, and black tea on ritodrine sulfation. Results. Sulfation of ritodrine by SULT1A3 was much higher than that by SULT1A1, suggesting that the bioavailability of ritodrine may be limited by intestinal SULT1A3. The ritodrine sulfation activities of SULT1A1 and SULT1A3 were significantly inhibited by all beverages examined at a concentration of 10%. Green tea and black tea exhibited potent inhibition; even at a concentration of 5%, they both inhibited SULT1A1 by 100% and SULT1A3 by ≥95%. Conclusion. Our results suggest that concomitant ingestion of beverages such as green tea and black tea may increase the bioavailability of orally administered ritodrine, and perhaps other β2-agonists, and lead to an increase in the clinical effects or adverse reactions. © 2005 Springer Science + Business Media, Inc.

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Functional analysis of organic cation transporter 3 expressed in human placenta

Sata R., Ohtani H., Tsujimoto M., Murakami H., Koyabu N., Nakamura T., Uchiumi T., Kuwano M., Nagata H., Tsukimori K., Nakano H., Sawada Y.

Journal of Pharmacology and Experimental Therapeutics （Journal of Pharmacology and Experimental Therapeutics） 315(2) （ 2 ） 888-895 - 895 2005年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00223565

The aim of this study is to investigate the placental transport mechanism of cationic compounds by comparison of the uptake of an organic cation into human placental basal membrane vesicles (BLMVs) with that into organic cation transporter 3 (OCT3)-expressing cells. Reverse transcription-polymerase chain reaction analysis demonstrated that OCT3 is the only OCT isoform expressed in the human placenta. The function of OCT3 was investigated by measuring the uptake of 1-methyl-4-phenylpyridinium (MPP+) into human embryonic kidney (HEK)293 cells stably expressing OCT3 (HEK/OCT3 cells). The OCT3-mediated uptake of MPP+ was sodium- and chloride-independent and saturable, with a Michaelis constant (Km) of 82.5 μM. The OCT3-mediated uptake was inhibited by various cationic drugs in a concentration-dependent manner but not by anionic compounds, such as p-aminohippuric acid and captopril, or a zwitterion, carnitine. Western blotting analysis of membrane vesicles prepared from human term placenta revealed that OCT3 is expressed only in BLMVs but not in microvillous membrane vesicles. The uptake of MPP+ into BLMVs was membrane potential-dependent and saturable, with a Km value of 51.8 μM, which is similar to that in HEK293/OCT3 cells. The inhibitory spectrum of various compounds on MPP+ uptake by BLMVs was also similar to that in HEK293/OCT3 cells. These results suggest that OCT3 is expressed on the basal membrane of human trophoblast cells and plays an important role in the placental transport of cationic compounds. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Physiologically based pharmacokinetic model for pralmorelin hydrochloride in rats

Nasu R., Kumagai Y., Kogetsu H., Tsujimoto M., Ohtani H., Sawada Y.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 33(10) （ 10 ） 1488-1494 - 1494 2005年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

Pralmorelin hydrochloride (pralmorelin), consisting of six amino acid residues, is a growth hormone-releasing peptide. The aim of this study is to analyze the pharmacokinetics of pralmorelin after intravenous bolus administration to rats, and to develop a physiologically based pharmacokinetic (PB-PK) model to describe and predict the concentrations of pralmorelin in blood and tissues. Pralmorelin (3 mg/kg) was administered intravenously to 24 Sprague-Dawley rats. Groups of three rats were sacrificed by decapitation at each designated time point (up to 4 h), and plasma and tissues (brain, lung, heart, liver, kidney, small intestine, muscle, adipose, and skin) were collected. Bile was also pooled until decapitation. The concentration of pralmorelin in samples was determined by liquid chromatography-tandem mass spectrometry. Plasma concentrations of pralmorelin declined rapidly in a biexponential manner. Biliary excretion of pralmorelin was so rapid that 80% of the dose was recovered unchanged in the bile within 1 h after administration. The distribution parameters in each tissue were obtained by using a hybrid model and an integration plot. They revealed that the distribution of pralmorelin into liver was blood flow-limited, and its distribution was permeability-limited in all other tissues. The PB-PK model developed in this study well described the time courses of pralmorelin concentration in the blood and tissues of rats. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Pharmacokinetic-pharmacodynamic analysis of antipsychotics-induced extrapyramidal symptoms based on receptor occupancy theory incorporating endogenous dopamine release.

Matsui-Sakata A., Ohtani H., Sawada Y.

Drug metabolism and pharmacokinetics （Drug metabolism and pharmacokinetics） 20(3) （ 3 ） 187-199 - 199 2005年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

We aimed to analyze the risks of extrapyramidal symptoms (EPS) induced by typical and atypical antipsychotic drugs using a common pharmacokinetic-pharmacodynamic (PK-PD) model based on the receptor occupancy. We collected the data for EPS induced by atypical antipsychotics, risperidone, olanzapine and quetiapine, and a typical antipsychotic, haloperidol from literature and analyzed the following five indices of EPS, the ratio of patients obliged to take anticholinergic medication, the occurrence rates of plural extrapyramidal symptoms (more than one of tremor, dystonia, hypokinesia, akathisia, extrapyramidal syndrome, etc.), parkinsonism, akathisia, and extrapyramidal syndrome. We tested two models, i.e., a model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition and a model not considering the endogenous dopamine release, and used them to examine the relationship between the D2 receptor occupancy of endogenous dopamine and the extent of drug-induced EPS. The model incorporating endogenous dopamine release better described the relationship between the mean D2 receptor occupancy of endogenous dopamine and the extent of EPS than the other model, as assessed by the final sum of squares of residuals (final SS) and Akaike's Information Criteria (AIC). Furthermore, the former model could appropriately predict the risks of EPS induced by two other atypical antipsychotics, clozapine and ziprasidone, which were not incorporated into the model development. The developed model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition may be useful for the prediction of antipsychotics-induced EPS.

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Functional induction and de-induction of P-glycoprotein by St. John's wort and its ingredients in a human colon adenocarcinoma cell line

Tian R., Koyabu N., Morimoto S., Shoyama Y., Ohtani H., Sawada Y.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 33(4) （ 4 ） 547-554 - 554 2005年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

Continuous use of St. John's wort decreases the bioavailabilities of a variety of drugs. This interaction is attributed to the induction of cytochrome P450 3A4 and/or P-glycoprotein. In this study, we aimed to examine the chronic effects of St. John's wort and its constituents, hyperforin and hypericin, on the expression and function of P-glycoprotein in an intestinal cell line, LS 180. We also examined the acute inhibitory effect of St. John's wort on P-glycoprotein by using LLC-GA5-COL150 cells, which overexpress P-glycoprotein. St. John's wort and hyperforin but not hypericin increased the expression of P-glycoprotein in LS 180 cells. Removal of St John's wort resulted in a restoration of P-glycoprotein level within 48 h. The content of hyperforin in St. John's wort extract was high enough to induce P-glycoprotein, suggesting that the induction of P-glycoprotein by St. John's wort can be almost attributable to hyperforin. The LS 180 cells chronically exposed to St. John's wort or hyperforin exhibited the increase in the function of P-glycoprotein assessed by the efflux of digoxin, and the activities correlated well with P-glycoprotein level. On the other hand, St. John's wort and its two constituents did not show any acute effect on P-glycoprotein-mediated transport of digoxin. St John's wort induced P-glycoprotein in vitro that functions as a drug efflux pump. Hyperforin is considered to be a primary cause of the inductive effect of St. John's wort. Long-term administration of St. John's wort may cause clinically significant decrease in the plasma concentrations of P-glycoprotein substrates. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Association between neuroleptic drug-induced extrapyramidal symptoms and dopamine D2-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 43(4) 163-171 2005年04月

研究論文（学術雑誌）, 共著, 査読有り

Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B

Satoh H., Yamashita F., Tsujimoto M., Murakami H., Koyabu N., Ohtani H., Sawada Y.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 33(4) （ 4 ） 518-523 - 523 2005年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

Human organic anion-transporting polypeptide B (OATP-B; OATP2B1) is expressed in the human intestinal epithelial cells, and is suggested to be involved in the intestinal absorption of anionic drugs in vivo. Although citrus juices have been shown to inhibit the function of human OATP-A (OATP1A2), the effect of citrus juices on the OATP-B function remains unclear. In this study, we aimed to examine the effects of citrus juices on the function of OATP-B. The effects of citrus juices on the uptake of estrone-3-sulfate, a typical substrate for OATP-B, into human embryonic kidney 293 cells stably expressing OATP-B were evaluated. Juices were diluted with uptake buffer, adjusted to pH 7.4 and approximately 300 mOsm, and used for the experiments. Grapefruit juice (GFJ) and orange juice (OJ) at a concentration of 5% significantly inhibited the OATP-B-mediated uptake of estrone-3-sulfate by 82 and 53%, respectively. Major constituents of GFJ and OJ also significantly inhibited the OATP-B-mediated uptake of estrone-3-sulfate. Glibenclamide, a hypoglycemic drug, was identified for the first time as a substrate for OATP-B with a Kt value of 6.26 μM. GFJ and OJ inhibited the OATP-B-mediated uptake of glibenclamide. These results suggest that citrus juices may inhibit the intestinal absorption of anionic drugs, such as glibenclamide, via the inhibition of OATP-B. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

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Improvement of dry mouth by replacing paroxetine with fluvoxamine

Arima Y., Kubo C., Tsujimoto M., Ohtani H., Sawada Y.

Annals of Pharmacotherapy （Annals of Pharmacotherapy） 39(3) （ 3 ） 567-571 - 571 2005年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10600280

OBJECTIVE: To present a case of improvement of paroxetine-induced dry mouth by substitution of fluvoxamine and analyze this case based on receptor occupancy theory. CASE SUMMARY: A 66-year-old woman with major depressive disorder had been treated with brotizolam 0.5 mg/day, flunitrazepam 2 mg/day, sulpiride 100 mg/day, bromazepam 2 mg/day, trazodone 25 mg/day, and paroxetine hydrochloride 10 mg/day. Although her psychological symptoms improved gradually, she complained of dry mouth. Paroxetine was replaced with fluvoxamine maleate 50 mg/day, and the dryness disappeared within a month. DISCUSSION: We calculated the time courses of muscarinic acetylcholine (mACh) receptor occupancy after oral administration of paroxetine and fluvoxamine at the treatment doses by using pharmacokinetic parameters obtained from the literature. The mACh receptor occupancy was estimated to be decreased from 0.22% to 0.020% by replacing paroxetine with fluvoxamine. CONCLUSIONS: The improvement of dry mouth observed after the replacement of paroxetine with fluvoxamine in this patient may have been due to a decrease in the mACh receptor occupancy.

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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年01月

研究論文（学術雑誌）, 共著, 査読有り, 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年01月

研究論文（学術雑誌）, 共著, 査読有り, 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年

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年12月

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年11月

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年08月

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年07月

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年06月

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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