研究者詳細 - 大谷　壽一

論文 - 大谷　壽一

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Kinetic analysis of the transport of salicylic acid, a nonsteroidal anti-inflammatory drug, across human placenta

Shintaku K., Arima Y., Dan Y., Takeda T., Kogushi K., Tsujimoto M., Nagata H., Satoh S., Tsukimori K., Nakano H., Hori S., Ohtani H., Sawada Y.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 35(5) （ 5 ） 772-778 - 778 2007年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

The aim of this study was to develop a pharmacokinetic model to describe the transplacental transfer of drugs, based on the human placental perfusion study. The maternal and fetal sides of human placentas were perfused with salicylic acid together with antipyrine, a passive diffusion marker. The drug concentration in the placental tissue was determined at the end of perfusion. A compartment model consisting of maternal space, fetal intravascular space, and placental tissue was fitted to the observed concentration profiles of salicylic acid in the maternal and fetal effluents. The developed model could adequately explain the concentration profiles of salicylic acid in the effluents with influx clearances from maternal and fetal perfusates to placental tissue of 0.0407 and 0.0813 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates (k2 and k3) of 0.0238 and 0.176 min-1, respectively. The kinetics of antipyrine was adequately described by assuming rapid equilibrium between fetal perfusate and placental tissue compartments. The influx plasma clearance from the maternal side (K″1) in humans was estimated by taking into account the protein binding. The K″1/k2 value of salicylic acid was 1.07 ml/g cotyledon and was larger than that of antipyrine (0.642 ml/g cotyledon). We evaluated the transplacental transfer kinetics of salicylic acid by human placental perfusion study with various perfusion protocols. Based on the data obtained, we developed a pharmacokinetic model, which should enable us to estimate the influx profile of drugs into umbilical arterial blood from the maternal plasma concentration profile. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.

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Assessment of alpha1-adrenoceptor antagonists in benign prostatic hyperplasia based on the receptor occupancy theory.

Ito K, Ohtani H, Sawada Y*.

British Journal of Clinical Pharmacology 63(4) 394-403 2007年04月

研究論文（学術雑誌）, 共著, 査読有り

Effect of macrolide antibiotics on uptake of digoxin into rat liver

Ito S., Nasu R., Tsujimoto M., Murakami H., Ohtani H., Sawada Y.

Biopharmaceutics and Drug Disposition （Biopharmaceutics and Drug Disposition） 28(3) （ 3 ） 113-123 - 123 2007年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01422782

The objective of this study was to examine the effect of macrolide antibiotics, clarithromycin, erythromycin, roxithromycin, josamycin and azithromycin, on the hepatic uptake of digoxin. The uptake of [3 H]digoxin was studied in rats in vivo, using the tissue-sampling single-injection technique, and in isolated rat hepatocytes in vitro. The uptake of [3H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (Km) of 445 nM. All the macrolide antibiotics inhibited the uptake of [3H]digoxin into rat hepatocytes in a concentration-dependent manner. However, clarithromycin did not affect the in vivo hepatic uptake of digoxin in rats. The in vivo permeability-surface area product of digoxin for hepatic uptake (PSinf) was estimated to be 12.5 ml/min/g liver from the present in vitro data, which is far larger than the hepatic blood flow rate (1.4 ml/ min/g liver). Macrolide antibiotics at clinically relevant concentrations inhibit digoxin uptake by rat hepatocytes in vitro, but not in vivo, probably because hepatic uptake of digoxin in rats is blood flow-limited. Clinically observed digoxin-macrolide interaction in humans could be due to macrolide inhibition of hepatic digoxin uptake, if the uptake is permeation-limited. Copyright © 2007 John Wiley & Sons, Ltd.

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Assessment of α<inf>1</inf>-adrenoceptor antagonists in benign prostatic hyperplasia based on the receptor occupancy theory

Ito K., Ohtani H., Sawada Y.

British Journal of Clinical Pharmacology （British Journal of Clinical Pharmacology） 63 （ 4 ） 394 - 403 2007年04月

ISSN 03065251

Aims: To assess the mechanistic relationship between doxazosin (α1-receptor antagonist) and receptor occupancy and a measure of pharmacological effect (Qmax, the maximum urinary flow rate) and to compare the mean receptor occupancy ratio at clinical doses of doxazosin, tamsulosin, terazosin and prazosin in benign prostatic hyperplasia (BPH). Methods: A ternary complex model, which described the mechanism of α1-receptor antagonists, was fitted to the pharmacological effects and receptor occupancy ratio data for doxazosin (standard tablet). In addition, mean receptor occupancy was calculated for other α1- receptor antagonists and the optimal receptor occupancy was evaluated. The clinical pharmacological effects of the controlled release formulation of doxazosin (doxazosin GITS) were estimated based on the receptor occupancy. Results: The mechanistic based model was able to describe the pharmacological effects of doxazosin. Regardless of the plasma concentrations or clinical dose of each drug, the results suggest that receptor occupancy is useful to assess quantitatively and compare the pharmacological effects of drugs with similar mechanisms of action. The clinical dosage for doxazosin GITS was estimated to be at least 8 mg and the stable pharmacological effect is expected based on the estimated receptor occupancy. Conclusions: A model for Qmax improvement in BPH based on the receptor occupancy theory was able to describe the clinical effects of the α1-receptor antagonists. Receptor occupancy is a useful index for predicting the clinical effects of α1-receptor antagonists. © 2006 The Authors.

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医薬品適正使用推進のためのWEBページを用いた薬剤師向けe-Learnigシステムの利用者による評価

佐田宏子, 大谷壽一, 矢崎泰三, 坂本浩己, 堀里子, 澤田康文

医薬品情報学（(一社)日本医薬品情報学会） 8 （ 4 ） 307 - 314 2007年02月

ISSN 1345-1464

e-Learningシステム(アリセプト処方せんチェックe-ラーニング)を構築した。構築・公開したe-Learningシステムの利用実態を把握するとともに、システムに対するユーザーの意見を調査した。会員薬剤師5766例に対して、電子メールで送信した。198件の回答が得られた。薬剤師としての経験年数が10年以上の薬剤師が約62%を占めた。開局薬局が67.7%であった。自己研鑚システムとして有用と評価され、継続したシステムの公開が期待されていると考えた。また、他の医薬品に関しても同様なシステムを望む回答者が多く、要望が多かった医薬品を対象に計画的に作成し、公開してゆくことが望ましいと考えられた。

薬薬連携に関するアンケート調査　疑義照会の現状と問題点

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） 8 （ 4 ） 296 - 301 2007年02月

ISSN 1345-1464

薬薬連携の中での疑義照会の現状と問題点を明らかにし、今後の疑義照会のあり方を探ることで適正な薬物治療を実施する上で有用な情報を構築することを目的にアンケート調査を行った。院外処方せんを発行する際に、処方鑑査を行っているかとの問いに関して、半数近くの47%が薬剤部の関与していないと回答した。院外処方せん発行後の〜次疑義照会先は薬剤部であるとの回答が74%を占め、一次疑義照会先を医師へ直接と決めている病院は12%にとどまった。保険薬局薬剤師の半数が、ほとんど近隣の医療機関からの処方せんを受けていると回答し、回答者の約98.5%が疑義照会の経験があると回答した。疑義照会先は、医師に電話(23.7%)、外来受付に電話、薬剤部に電話ほぼ同程度であった。疑義照会の内容としては、用法の不備、規格、単位の不備が大多数を占めた。

Antacid interaction with new quinolones: dose regimen recommendations based on pharmacokinetic modeling of clinical data for ciprofloxacin, gatifloxacin and norfloxacin and metal cations.

Miyata K, Ohtani H, Tsujimoto M, Sawada Y*.

International Journal of Clinical Pharmacology and Therapeutics 45(1) 63-70 2007年01月

研究論文（学術雑誌）, 共著, 査読有り

Antacid interaction with new quinolones: Dose regimen recommendations based on pharmacokinetic, model of clinical data for ciprofloxacin, gatifloxacin and norfloxacin and metal cations

Miyata K., Ohtani H., Tsujimoto M., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics （International Journal of Clinical Pharmacology and Therapeutics） 45 （ 1 ） 63 - 70 2007年01月

ISSN 09461965

Objective: New quinolones (NQs) are wily used to treat various infections. However, concomitant oral administration of metal cations may decrease absorption of NQs and consequently decrease their blood concentration and pharmacological effect. A convenient approach to avoid this interaction is to separate the dosages by a certain interval. In this study, we aimed to develop a novel pharmacokinetic model to describe NQs-metal cation interactions in order to estimate the optimal dosing interval. Methods: Plasma concentration-time profiles of NQs after administration without or with metal cations at various dosing intervals were collected from the literature and analyzed with a pharmacokinetic model incorporating the formation ofNQs-metal cations complex. The model was fitted to the reported time profiles of ciprofloxacin (CPFX) plasma concentration after concomitant administration with aluminum hydroxide/ magnesium hydroxide antacid (Al/Mg antacid; Maalox, Maalox70) at various dosing intervals to obtain the pharmacokinetic parameters of CPFX. Model analysis was also carried out for gatifloxacin (GFLX) and norfloxacin (NFLX). Results: The developed model could adequately explain the interactions in all the combinations investigated. The model predicted, in the cases of usual doses of CPFX with Maalox, GFLX with Maalox70 and NFLX with sucralfate, that the NQ should be administered 4.5, 4.5 and 3.5 hours after, or 1, 1 and 0.5 hours before the administration of metal cations, respectively, to ensure 90% of control absorption. Conclusions: The developed model can adequately describe the extent of interaction between NQs and metal cations, and should be clinically useful to design dosage regimens to circumvent the interaction. © 2007 Dustri-Verlag Dr. K. Feistle.

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Inhibitory effects of angiotensin II receptor antagonists and leukotriene receptor antagonists on the transport of human organic anion transporter 4

Yamashita F., Ohtani H., Koyabu N., Ushigome F., Satoh H., Murakami H., Uchiumi T., Nakamura T., Kuwano M., Tsujimoto M., Sawada Y.

Journal of Pharmacy and Pharmacology （Journal of Pharmacy and Pharmacology） 58(11) （ 11 ） 1499-1505 - 1505 2006年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00223573

Human organic anion transporter 4 (OAT4) is the only member of the OAT family that is expressed in the placenta and also expressed in kidney. Although OAT4 has been shown to transport certain organic anions as well as other members of the OAT family, fewer numbers of substrates have been identified for OAT4 compared with OAT1 and OAT3, suggesting that the substrate specificity of OAT4 is greater than other OAT members. However, the substrate specificity of OAT4 remains to be investigated in detail. The aim of this study was to examine the effects of various drugs on the OAT4-mediated transport of estrone-3-sulfate, a typical substrate of OAT4, by using human embryonic kidney cells stably transfected with OAT4 (HEK-OAT4). HEK-OAT4 cells exhibited concentration- dependent uptake of estrone-3-sulfate, with a Km value of 20.9±3.53 μM. Dehydroepiandrosterone sulfate and probenecid potently inhibited estrone-3-sulfate uptake. We also searched for the potential inhibitors of OAT4 and identified candesartan, candesartan cilexetil, losartan, losartan carboxyl (EXP3174) and valsartan as inhibitors of OAT4, with K i values of 88.9, 135.2, 24.8, 13.8 and 19.6 μM, respectively. The above angiotensin II receptor antagonists and leukotriene receptor antagonists share a common structural feature, that is the tetrazole group. Although pranlukast is devoid of anionic motifs other than the tetrazole group, it potently inhibited the OAT4-mediated uptake of estrone-3-sulfate, indicating that a tetrazole group may be one important structural feature in substrate recognition by OAT4. © 2006 The Authors.

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モルヒネ製剤の剤形変更時の薬剤師の対応に関する研究

久澄礼子, 大谷壽一, 堀里子, 澤田康文

医薬品情報学（(一社)日本医薬品情報学会） 8 （ 3 ） 205 - 211 2006年11月

ISSN 1345-1464

薬剤師に対するアンケート調査を実施し、モルヒネ製剤の剤形変更時の処方チェックや投与設計に関して、薬剤師がどのように対応したいと考えているか調査した。モルヒネ製剤の剤形変更時の処方設計を支援するための専用アプリケーションが必要であった。アンケート調査により、半数以上の薬剤師が、モルヒネ製剤の剤形変更時の処方チェックおよび投与設計を添付文書の用法・用量との照合、モルヒネ換算比・等鎮痛用量比との照合で行っていた。モルヒネ製剤の剤形変更時の処方チェックを薬物動態シミュレーション等に基づいて行いたいと考えているものの実践できていないことが示された。薬物動態シミュレーションに基づいた処方設計支援システムの構築は、薬剤師の現状の問題点を解決する有用な手段であることが示唆された。

適正な処方設計・調剤支援システムのための医薬品製剤情報の規格化

佐田宏子, 大谷壽一, 澤田康文

医療情報学（(一社)日本医療情報学会） 26 （ 3 ） 209 - 215 2006年10月

ISSN 0289-8055

処方設計支援や処方チェックシステムの構築にあたっては、医薬品情報は、システム上でテキストとして保持されているだけでは不十分であり、利用状況を考慮に入れた適正な規格化が行われている必要がある。本研究においては、医薬品の製剤特性に基づいた処方設計支援機能を提供するために必要な医薬品情報を抽出、整理するとともに、それらを規格化するための基準と、適正に保持できるデータベース(DB)の構造を設計することを目的とした。既存の医薬品102種について、製剤特性や剤形加工後の安定性などのデータを収集し、我々がすでに報告した処方チェックパターンと照合して解析することによって、最適なDBのフォーマットを設計するとともに、剤形加工の可否について、DBに収載するための規格化基準を作成した。設計したDB構造と規格化基準を、それらの設計や構築に用いた薬剤とは異なる既存の88種の医薬品に適用したところ、処方設計支援に必要な製剤特性情報をもらすことなく収載することができた。今回構築したDBは、医薬品の製剤特性情報を適正に保持し、処方薬に対する錠剤の粉砕などの可否をチェックするシステムに利用できると考えられた。今回設計した製剤特性・剤形加工DBは、処方チェックおよび処方設計支援システムの構築に有用な基盤を提供すると考えられる。(著者抄録)

Dosage adjustment of quinolone antibiotics and angiotensin-converting enzyme inhibitors in patients with renal dysfunction

Ohtani H., Kinoshita Y., Nagasaki Y., Sata H., Miki A., Tsujimoto M., Sawada Y.

International Journal of Clinical Pharmacology and Therapeutics （International Journal of Clinical Pharmacology and Therapeutics） 44(9) （ 9 ） 428-437 - 437 2006年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09461965

The aim of this study was to verify an approach for calculating pharmacokinetic parameters suitable for adjusting dosage regimens in patients with renal dysfunction. We carried out a retrospective analysis of the pharmacokinetic profiles of 12 new quinolone antibiotics and 11 angiotensin-converting enzyme inhibitors (ACEIs) in patients with normal and impaired renal function to obtain the renal excretion ratio (Rrenal) of each drug. We demonstrated that the pharmacokinetics of each drug in a patient with renal dysfunction can be adequately estimated using the Rrenal value of each drug together with the creatinine clearance as an index of the individual's renal function. Using the Rrenal value obtained, we could successfully simulate pharmacokinetic profiles of the drugs in publications other than that used to obtain the Rrenal values. On the other hand, age-related changes in the pharmacokinetics of new quinolone antibiotics are not always adequately predicted using the Rrenal value compared to using creatinine clearance alone as an index, and the reasons for this are not fully understood. These results demonstrate that dosage regimens of quinolone antibiotics and ACEIs in patients with renal dysfunction can be adequately optimized using the Rrenal value for each drug using the present approach. © 2006 Dustri-Verlag Dr. K. Feistle.

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Major determinant factors of the extent of interaction between grapefruit juice and calcium channel antagonists

Ohnishi A., Ohtani H., Sawada Y.

British Journal of Clinical Pharmacology （British Journal of Clinical Pharmacology） 62(2) （ 2 ） 196-199 - 199 2006年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03065251

Aim: To evaluate quantitatively the influence of bioavailability and plasma unbound fraction (fu) on the extent of interaction between grapefruit juice (GFJ) and calcium antagonists. Methods: The extent of drug-GFJ interaction was evaluated from reported clinical interaction studies of 11 calcium antagonists. The relationship between extent of interaction and bioavailability or fu was analysed. Results: The following significant hyperbolic relationships were observed: [Extent] = 12.2/[bioavailability] + 1 and [Extent] = 0.718/[fu ] + 1. Conclusions: Bioavailability and fu are major determinant factors of calcium antagonist-GFJ interaction: a drug with smaller bioavailability or lower fu is likely to exhibit a more potent interaction, and vice versa. © 2006 Blackwell Publishing Ltd.

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服薬ノンコンプライアンス時の薬剤師の対応に関する実状と問題点

久澄礼子, 大谷壽一, 三木晶子, 堀里子, 澤田康文

医薬品情報学（(一社)日本医薬品情報学会） 8 （ 2 ） 133 - 138 2006年08月

ISSN 1345-1464

薬剤師間情報交換・研修システムに登録していた薬剤師4106名を対象に、電子メールを用いて患者のノンコンプライアンスへの対応に関するアンケート調査を行った。99.0%の薬剤師がノンコンプライアンス症例を経験し、そのうち75.5%が患者にノンコンプライアンス後の対処法を指示した経験があった。どのようにして対処法を決定したかについては、「次回から処方どおり服用するように指示した」が最も多く、「薬物動態シミュレーション等により血中濃度または薬効の経時的変化を計算して指示した」は2.6%のみであった。しかし、薬物動態シミュレーション等による投与設計で対応をしなかった薬剤師の57.5%が「対処法は適切だった」と回答した。対処法を決定する際の問題点については、「薬物動態シミュレーション等により対処すれば良いと考えたが、具体的な方法がわからなかった」が最も多く、問題点を解決するための要望については、「対処法について投与設計できるシステムが欲しい」が最も多かった。

処方オーダリングシステムの入力方法と操作性における問題点　医師に対するアンケート調査

佐田宏子, 大谷壽一, 折井孝男, 澤田康文

医療薬学（(一社)日本医療薬学会） 32 （ 7 ） 679 - 685 2006年07月

ISSN 1346-342X

医師を対象としたアンケート調査によって,処方オーダリングシステムの使用実態とその操作性に対する医師の意識を明らかにし,処方オーダリングシステムにおけるヒューマン・マシンインターフェース(HMI)が具備すべき要件を検討した.「薬剤師間情報交換・研修システム」の会員薬剤師の中から,病院薬剤師を抽出し,医師に対する処方オーダリングシステムについてのアンケート調査を行った.17医療施設中,9施設は処方薬の候補リストの表示に必要な入力文字数が2文字以下で,最低入力文字数をシステムによって3文字にすることが必要と考えられた.処方オーダリングシステム導入による弊害として,医薬品名の不確実な認識に起因する処方オーダリングミスの発生が危惧された.投与量チェックシステムは,否定的な意見は少なく,投薬ミス防止のため標準で具備すべき機能であると考えられた.特定服用時点の限定システムが組み込まれている施設は3施設であった

Pharmacokinetic modelling of the interaction between St John's wort and ciclosporin A

Murakami Y., Tanaka T., Murakami H., Tsujimoto M., Ohtani H., Sawada Y.

British Journal of Clinical Pharmacology （British Journal of Clinical Pharmacology） 61(6) （ 6 ） 671-676 - 676 2006年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03065251

Aims: St John's wort (SJW) decreases the blood concentration of ciclosporin A (CsA), which may result in allograft rejection. In addition, the time course of this interaction is not parallel with the administration of SJW. We aimed to develop a pharmacokinetic model to predict the time profile of blood CsA concentrations during and after the intake of SJW. Methods: We developed a pharmacokinetic model incorporating turnover of detoxicating proteins, with the assumption that the amount of detoxicating proteins is in inverse proportion to the ratio of trough blood concentration to daily dose (C/D ratio) of CsA. First, we collected time profiles of blood CsA during and after the intake of SJW from the literature. Next, we analysed the relationship between D/C ratio and the daily dose of SJW at steady state. Subsequently, the developed model was simultaneously fitted to the time profiles of C/D ratios by using a nonlinear least-squares method to obtain model parameters. Results: The model analysis revealed that the induction of the detoxicating proteins by SJW was saturable with an elimination rate constant of the detoxicating proteins (ke) of 4.72 month-1. Elimination half-life of the detoxicating proteins calculated from the ke value was 4.4 days, suggesting that the dose of CsA should be carefully monitored for up to 2 weeks after the cessation of SJW intake. Conclusions: The present model may provide additional information for use in identifying optimal dosage regimens of CsA during and after the intake of SJW to prevent an adverse drug interaction between CsA and SJW. © 2006 Blackwell Publishing Ltd.

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The canine CYP1A2 deficiency polymorphism dramatically affects the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]-pyrimidine-2-(1H) -one (YM-64227), a phosphodiesterase type 4 inhibitor

Tenmizu D., Noguchi K., Kamimura H., Ohtani H., Sawada Y.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 34(5) （ 5 ） 800-806 - 806 2006年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

In a previous study, it was shown that the novel canine single nucleotide polymorphism (SNP) CYP1A2 1117C>T yields an inactive enzyme. In this study, the effect that this SNP has on the pharmacokinetics of 4-cyclohexyl-1-ethyl-7- methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227) was investigated. Plasma concentrations of the unchanged drug and five of its metabolites (MM-1 to MM-5) were determined after either intravenous or oral administration of YM-64227 to genotyped dogs (C/C, C/T, and T/T groups). Liver microsomes were prepared from these dogs to determine the in vitro metabolic clearance of YM-64227. After a single oral administration, the maximum plasma concentration and absolute bioavailability of YM-64227 in the T/T group were 17.1 times and 27.2 times higher than those in the C/C group, respectively, whereas the pharmacokinetics of YM-64227 after intravenous administration were not affected by genotype. The metabolic profiles in the T/T group were quite distinct from the others; i.e., the main metabolite was MM-2 in the C/C group, whereas MM-1 and MM-5 were the main metabolites in the T/T group. The formation clearances of MM-2 and MM-3 in the microsomes derived from T/T type dogs were significantly lower, whereas those of MM-1, MM-4, and MM-5 were not affected. A statistically significant correlation was observed between the in vivo and in vitro metabolic intrinsic clearances (r = 0.82, p < 0.001). The canine CYP1A2 1117C>T SNP proved to be responsible for a substantial portion of the interindividual variability in the pharmacokinetics of YM-64227. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.

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WEBページを用いた薬剤師向け実践的知識修得型e-Learningシステムの開発

佐田宏子, 大谷壽一, 矢崎泰三, 坂本浩己, 堀里子, 澤田康文

医薬品情報学（(一社)日本医薬品情報学会） 8 （ 1 ） 13 - 19 2006年05月

ISSN 1345-1464

医薬品の取り違えミスを防止するための薬名類似度の定量的指標の構築

大谷壽一, 竹田正幸, 今田結城, 澤田康文

薬学雑誌（(公社)日本薬学会） 126 （ 5 ） 349 - 356 2006年05月

ISSN 0031-6903

投薬ミスを防止するために薬名の類似度を計数化することを試みた.2薬名間の共通文字列部分が長いほど類似度が高いと考え,断片パターン指標を応用した指標を導入した.「共通文字列の連続性」,「先頭・末尾部分の重要性」の係数を配分した指標1,これら2係数に更にカタカナの文字形状の類似性係数を導入した指標2,音韻の類似性係数を導入した指標3を構築した.実際に医薬品名の取り違えが生じた227例を正例とし,負例は無作為に作成した2270組を用いて指標の評価を行った.既に報告されている指標として,薬名の特徴をベクトル化したcos1,先頭・末尾2文字のみに着目したhtcoと比較した.指標1,2,3はいづれもcos1,htcoよりも優れた評価関数値を示し,特に指標2が最良であった.指標2の偽陽性率,偽陰性率はcos1よりも著しく改善された.この指標は薬名に基づく医療ミスを防止する上で重要な情報を提供すると考えられた

Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B

Fuchikami H., Satoh H., Tsujimoto M., Ohdo S., Ohtani H., Sawada Y.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 34(4) （ 4 ） 577-582 - 582 2006年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

Most known interactions between herbal extracts and drugs involve the inhibition of drug-metabolizing enzymes, but little is yet known about the possible role of transporters in these interactions. In this study, we have examined the effects of herbal extracts used in dietary supplements on the function of organic anion-transporting polypeptide B (OATP-B; OATP2B1), which is expressed on human intestinal epithelial cells and is considered to be involved in the intestinal absorption of various drugs. Specifically, the effects of 15 herbal extracts on uptake of estrone-3-sulfate, a typical OATP-B substrate, by human embryonic kidney 293 cells stably expressing OATP-B were evaluated. At concentration levels considered likely to be attainable in the human intestine, extracts of bilberry, echinacea, green tea, banaba, grape seed, ginkgo, and soybean potently inhibited estrone-3-sulfate uptake by 75.5, 55.5, 82.1, 61.1, 64.5, 85.4, and 66.8%, respectively (P < 0.01). The inhibitory effect of ginkgo leaf extract was concentration-dependent (IC50 = 11.2 ± 3.3 μg/ml) and reversible. Moreover, flavonol glycosides and catechins significantly inhibited the function of OATP-B, suggesting that the inhibitory effects of the herbal extracts on OATP-B may be primarily attributable to flavonoids. The extracts of mulberry, black cohosh, and Siberian ginseng moderately (but significantly) inhibited estrone-3-sulfate uptake by 39.1, 47.2, and 49.2%, respectively (P < 0.05). Extracts of barley, Job's tears, rutin, rafuma, and passionflower were ineffective. These results suggest that coadministration of some dietary supplements may decrease the absorption of orally administered substrates of OATP-B. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.

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