Details of a Researcher - Ohtani, Hisakazu

Papers - Ohtani, Hisakazu

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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 2006.08

Research paper (scientific journal), Joint Work, Accepted, 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 2006.08

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 2006.07

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 2006.06

Research paper (scientific journal), Joint Work, Accepted, 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 2006.05

Research paper (scientific journal), Joint Work, Accepted, 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 2006.05

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 2006.05

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 2006.04

Research paper (scientific journal), Joint Work, Accepted, 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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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 2006.04

Research paper (scientific journal), Joint Work, Accepted, 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 2006.02

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 2005.10

Research paper (scientific journal), Joint Work, Accepted, 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 2005.09

Research paper (scientific journal), Joint Work, Accepted, 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 2005.08

Research paper (scientific journal), Joint Work, Accepted, 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 2005.08

Research paper (scientific journal), Joint Work, Accepted, 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 2005.07

Research paper (scientific journal), Joint Work, Accepted, 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 2005.06

Research paper (scientific journal), Joint Work, Accepted, 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 2005.04

Research paper (scientific journal), Joint Work, Accepted, 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 2005.04

Research paper (scientific journal), Joint Work, Accepted

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 2005.04

Research paper (scientific journal), Joint Work, Accepted, 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 2005.02

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