論文 - 大谷　壽一

災害時における薬物治療の注意点-「薬が飲めない使えない」「生活・体調の変化」に対応した薬学的管理-.

澤田康文, 三木晶子, 堀 里子, 佐藤宏樹, 大谷壽一, 大津史子.

日本病院薬剤師会雑誌 （日本病院薬剤師会）  47(9)   1101-1113 2011年09月

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Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants

Akiyoshi T., Saito T., Murase S., Miyazaki M., Murayama N., Yamazaki H., Guengerich F.P., Nakamura K., Yamamoto K., Ohtani H.

Drug Metabolism and Disposition （Drug Metabolism and Disposition）  39(4) （ 4 ） 724-8 - 728 2011年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00909556

　概要を見る

CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the Ki value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the Ki value for CMD was 0.64-fold lower. In CYP3A4.16, the Ki value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the Ki value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the Ki values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

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下痢で薬の体内動態はどう変わる?.

大谷壽一.

薬局 （南山堂）  62(3)   378-383 2011年03月

単著

未来先導型の研究と教育を目指して.

大谷壽一, 秋好健志.

薬剤学 （薬剤学）  70(4)   218-223 2010年07月

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代謝酵素が関係した相互作用 パロキセチンとCYP2D6代謝薬剤.

大谷壽一.

薬局 （南山堂）  61(8)   2803-2807 2010年07月

単著

併用禁忌・併用注意とは? どう決まる? どう判断する?.

大谷壽一, 佐藤宏樹, 澤田康文.

薬局 （南山堂）  61(8)   2767-2775 2010年07月

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類似名称による医薬品取り違え事故防止の試み.

玉木啓文, 堀 里子, 佐藤宏樹, 三木晶子, 大谷壽一, 澤田康文.

日本病院薬剤師会雑誌 （日本病院薬剤師会）  46(6)   765-769 2010年06月

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Pharmacokinetic modeling of the dosing interval dependency of the interaction between itraconazole and triazolam.

Toi A, Ohtani H, Tsujimoto M, Sawada Y*.

Int J Clin Pharmacol Ther 48(6)   356-366 2010年06月

研究論文（学術雑誌）, 共著, 査読有り

Pharmacokinetic modeling of the dosing interval dependency for the interaction between itraconazole and triazolam

Toi A., Ohtani H., Tsujimoto M., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics （International Journal of Clinical Pharmacology and Therapeutics）  48 （ 6 ） 356 - 366 2010年06月

ISSN  09461965

　概要を見る

Objective: Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A with an elimination half-life of more than 30 hours. Therefore, itraconazole may cause persistent CYP3A inhibition. Triazolam is primarily metabolized by CYP3A and its plasma concentration is increased remarkably by itraconazole. Although separating their dosages by 24 hours has been shown to reduce the interaction, an appropriate dosage interval remains to be determined. The aim of this study was to identify an appropriate dosage schedule to avoid their interaction. Materials and methods: We developed a pharmacokinetic model based on the assumption that both itraconazole and hydroxyitraconazole competitively and reversibly inhibit the first-pass metabolism and systemic elimination of triazolam. The developed model was simultaneously fitted to the plasma concentration profiles of triazolam, taken fromthe literature, by using the plasma concentration-time profiles of itraconazole and hydroxyitraconazole as input functions to estimate their in vivo Ki values. Subsequently, we simulated the plasma concentration profiles of triazolam administered after itraconazole therapy with various dosing intervals. Results: The model could explain and simulate the interaction between itraconazole-triazolam using a variety of dosage intervals between the administrations. Conclusions: The developed model may provide useful information with regard to the appropriate interval for triazolam administration during itraconazole therapy. ©2010 Dustri-Verlag Dr. K. Feistle.

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Saturable binding of finasteride to steroid 5-alpha-reductase as determinant of nonlinear pharmacokinetics.

Suzuki R, Satoh H, Ohtani H, Hori S, Sawada Y*.

Drug Metabol Pharmacokinet 25(2)   208-213 2010年04月

研究論文（学術雑誌）, 共著, 査読有り

Inhibitory effects of herbal extracts on breast cancer resistance protein (BCRP) and structure-inhibitory potency relationship of isoflavonoids

Tamaki H., Satoh H., Hori S., Ohtani H., Sawada Y.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics）  25(2) （ 2 ） 170-179 - 179 2010年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13474367

　概要を見る

The inhibition of intestinal breast cancer resistance protein (BCRP), which restricts the absorption of xenobiotics, may increase the systemic availability of its substrates. The aim of this study was to evaluate the inhibitory effects of herbal extracts and their constituents on BCRP-mediated transport. The inhibitory effects of 9 herbal extracts and 23 isoflavonoids, including soybean-derived isoflavones, on BCRP-mediated methotrexate (MTX) transport were evaluated using BCRP-expressing membrane vesicles. The structure-in-hibitory potency relationship was investigated by multiple factor analysis. Extracts of soybean, Gymnema sylvestre, black cohosh and passion flower and rutin strongly inhibited BCRP-mediated transport of MTX at 1 mg/ml, while inhibition by chlorella, milk thistle and Siberian ginseng extracts was weak. Among the 23 isoflavonoids examined, all of which inhibited BCRP-mediated transport, coumestrol showed the most potent inhibition (IC50=63 nM). The inhibitory potencies of 6 isoflavonoid glucosides were 10-to 100-fold lower than those of the corresponding aglycones. The addition of a 5-hydroxyl or 6-methoxyl moiety tended to potentiate the inhibition. The inhibitory potency of daidzein was decreased 100-fold by 7-glucuronidation, but was virtually unaffected by 4′-sulfation. Thus, some herbal and dietary supplements and isoflavonoids may increase the systemic availability of BCRP substrates when concomitantly given orally.

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大谷壽一.

医薬品情報学 （日本医薬品情報学会）  11(3)   192-195 2010年02月

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Saturable binding of finasteride to steroid 5a-reductase as determinant of nonlinear pharmacokinetics

Suzuki R., Satoh H., Ohtani H., Hori S., Yasufumi S.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics）  25 （ 2 ） 208 - 213 2010年

ISSN  13474367

　概要を見る

Finasteride, a steroid 5a-reductase (5aR) inhibitor, is used to treat benign prostatic hyperplasia and androgenetic alopecia. We aimed to develop a pharmacokinetic/pharmacodynamic model to explain its nonlinear pharmacokinetics and describe the serum concentration profile of dihydrotestosterone (DHT) after finasteride administration. We developed a pharmacokinetic model incorporating a compartment that represents the binding of finasteride to 5aR. We fitted this model to the time-concentration profiles of finasteride after repeated administration of finasteride 0.2 and 1 mg/day. We constructed a pharmacodynamic model considering the inhibition of 5aR type I and type II (5aR1 and 5aR2). This model was fitted to the time profiles of serum DHT. The developed pharmacokinetic model well described nonlinear increase in AUC after repeated administration of finasteride. The association and dissociation rate constants were estimated to be 0.0293/nmol/hr and 0.0185/hr, respectively. Pharmacodynamic model analysis suggested that the 5aR1 inhibition is dose-dependent in the dose range from 0.2 to 100 mg, while the 5aR2 inhibition is almost saturated in the same dose range. Finasteride's saturable binding to 5aR2 is the likely cause of its nonlinear pharmacokinetics. The developed pharmacokinetic/pharmacodynamic model should allow prediction of plasma concentration profiles of finasteride and DHT.

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医薬品情報学研究のあり方-ワークショップにおけるKJ法に基づく問題抽出と解析-.

山田安彦, 澤田康文*, 山本康次郎, 飯久保尚, 大谷壽一, 上村直樹, 安部好弘, 上原恵子, 太田隆文, 折井孝男, 岸本紀子, 齋藤充生, 武立啓子, 樽野弘之, 近澤洋平, 仲佐啓詳, 橋口正行, 堀 里子, 山元俊憲.

医薬品情報学 （(一社)日本医薬品情報学会）  11(2) （ 2 ） 76-87 - 87 2009年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1345-1464

　概要を見る

日本医薬品情報学会(JASDI)は医薬品情報学のあり方を提言することを目的に、ビジョン委員会を発足させた。当該委員会では医薬品情報学の教育が抱える問題点を、KJ法を用いて抽出、明確化することを目的に、2008年7月の第11回JASDI学会においてワークショップを開催した。抽出された大きな問題点は「医薬品情報の範囲が広すぎること」と「医薬品情報の定義とシステムが不明確なこと」であった。関連する問題点は歴史の浅さと独自性の欠如であった。また、研究の方法論が十分に確立していないこと、教育のシステム化ができていないことも指摘された。本ワークショップにより、医薬品情報学の抱える「本学問の定義づけ、体系化ができていない」という問題点が明確化すると共に、参加者に対しても有意な意識変化をもたらしたことが明らかになった。

患者の健康食品使用に関する薬剤師の行動実態調査.

朝比奈泰子, 堀 里子, 大谷壽一, 澤田康文.

医療薬学 （(一社)日本医療薬学会）  35(10) （ 10 ） 685-692 - 692 2009年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1346-342X

　概要を見る

臨床現場の薬剤師が患者の健康食品使用に対してどのように関わっているのか、また、健康食品情報の収集状況、被害情報の収集・アウトプットといった行動の現状を明らかにすることを目的として、著者らが2000年より構築・運営しているインターネットによる全国薬剤師間情報交換・研修システムi-PHISSを介してアンケートを行った。323名から回答が得られ、内訳は薬局薬剤師219名、病診薬剤師104名であった。処方箋受付時に患者の健康食品使用の有無を確認するか?という薬局薬剤師への問いに対して、「必ず確認する」と回答した人が29%、「必要に応じて確認する」が58%、「患者からの申し出がない限り確認しない」が12%であった。入院患者に健康食品使用の有無を確認するか?という病診薬剤師への問いに対して、「必ず確認する」と回答した人が44%、「必要に応じて確認する」が32%、「患者からの申し出がない限り確認しない」が10%であった。

医療従事者を対象として定期的に健康食品情報を提供するインターネット研修システムの構築とその評価.

朝比奈泰子,堀 里子,大谷壽一,澤田康文*.

薬学雑誌 （(公社)日本薬学会）  129(6) （ 6 ） 773-780 - 780 2009年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0031-6903

　概要を見る

著者らは、2000年より薬剤師間情報交換・研修システム「Internet-based Pharmacist's Information-Sharing System(i-PHISS)」、2005年より医師間情報交換・研修システム「Internet-based Medical Doctor's Information-Sharing System(i-MEDISS)」を構築・運用してきた。これらシステムは、医療従事者の知識・技能・態度の研鑽、医療ミスの低減を目的として、インターネットを介して医療従事者から臨床現場で起きた医薬品に関するアクシデント・インシデント事例を収集し、それら事例にエビデンスに基づく検討・解説を加えて再度配信する登録制のシステムである。今回、両システムを活用して、医薬品のみならず健康食品に関しても医療従事者のニーズに沿った情報コンテンツを作成し、定期的な提供を行うようにした。このサービスに対するi-PHISS・i-MEDISS登録者の評価をウェブアンケートによって調査した結果、概ね好評であり、健康食品に対する医療従事者の関心を喚起できていたことが確認された。

Quantitative comparison of the convulsive activity of combinations of twelve fluoroquinolones with five nonsteroidal antiinflammatory agents

Kim J., Ohtani H., Tsujimoto M., Sawada Y.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics）  24(6) （ 2 ） 167-174 - 174 2009年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13474367

　概要を見る

Concomitant administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs) induces serious convulsion in humans. There are differences in convulsive activity among fluoroquinolones and in the potentiation of fluoroquinolone-induced convulsion among NSAIDs, but a comprehensive, quantitative comparison has not been carried out. This study evaluates the inhibitory effects of twelve fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pazufloxacin, prulifloxacin, sparfloxacin, and tosufloxacin) alone or in the presence of an NSAID (4-biphenylacetic acid, diclofenac sodium, loxoprofen, lornoxicam or zaltoprofen) on the GABAA receptor binding of [3H]muscimol in an in vitro study using mice synaptic plasma membrane. The rank order of inhibitory effects of the fluoroquinolones was prulifloxacin≈norfloxacin> ciprofloxacin≥enoxacin>gatifloxacin≥ ofloxacin≈tosufloxacin≈lomefloxacin> levofloxacin≥sparfloxacin≥ pazufloxacin≈fleroxacin. 4-Biphenylacetic acid most potently enhanced the inhibitory effects of the fluoroquinolones, while zaltoprofen, loxoprofen, lornoxicam and diclofenac had essentially no effect. The clinical risk of convulsion for each combination was estimated using a pharmacodynamic model based on receptor occupancy using the in vitro data set obtained and pharmacokinetic parameters in humans collected from the literature. The combinations of 4-biphenylacetic acid with prulifloxacin and enoxacin were concluded to be the most hazardous.

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Transplacental pharmacokinetics of diclofenac in perfused human placenta.

Shintaku K., Hori S., Tsujimoto M., Nagata H., Satoh S., Tsukimori K., Nakano H., Fujii T., Taketani Y., Ohtani H., Sawada Y.

Drug metabolism and disposition: the biological fate of chemicals （Drug metabolism and disposition: the biological fate of chemicals）  37 （ 5 ） 962-968 - 968 2009年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0090-9556

　概要を見る

The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of L-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with L-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPT(ss) value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of L-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min(-1), respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with L-lactic acid.

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Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy

Suzuki K., Doki K., Homma M., Tamaki H., Hori S., Ohtani H., Sawada Y., Kohda Y.

British Journal of Clinical Pharmacology （British Journal of Clinical Pharmacology）  67(1) （ 1 ） 44-49 - 49 2009年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03065251

　概要を見る

AIM: To assess whether or not co-administration of proton pump inhibitors (PPIs) is a risk factor for delayed elimination of plasma methotrexate (MTX) in high-dose MTX (HDMTX) therapy for malignant diseases. METHODS: To assess the effects of PPI co-administration on elimination of plasma MTX, we examined plasma MTX concentration data on 171 cycles of HDMTX therapy performed in 74 patients. We performed multiple logistic regression analysis to evaluate PPI co-administration as a risk factor. Inhibitory potencies of omeprazole, lansoprazole, rabeprazole and pantoprazole on MTX transport via breast cancer resistance protein (BCRP, ABCG2) were also investigated in an in vitro study using membrane vesicles expressing human BCRP. RESULTS: We identified co-administration of PPIs as a risk factor for delayed elimination (odds ratio 2.65, 95% confidence interval 1.03, 6.82) as well as renal and liver dysfunction. All four PPIs inhibited BCRP-mediated transport of MTX, with half-maximal inhibitory concentrations of 5.5-17.6 μM - considerably higher than the unbound plasma concentrations of the PPIs. CONCLUSIONS: Our results support previous findings suggesting that PPI co-administration is associated with delayed elimination of plasma MTX in patients with HDMTX therapy. This drug interaction, however, cannot be explained solely by the inhibitory effects of PPIs on BCRP-mediated MTX transport. © 2008 The Authors.

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Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine-alprazolam interaction in patients with psychosomatic disease

Sugahara H., Maebara C., Ohtani H., Handa M., Ando K., Mine K., Kubo C., Ieiri I., Sawada Y.

European Journal of Clinical Pharmacology （European Journal of Clinical Pharmacology）  65 （ 7 ） 699-704 - 704 2009年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00316970

　概要を見る

Purpose: Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP). Methods: Blood samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also genotyped for CYP2D6. Results: The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged. Conclusions: The extent of interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers. © 2009 Springer-Verlag.

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