Details of a Researcher - Ohtani, Hisakazu

Papers - Ohtani, Hisakazu

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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

ISSN 13474367

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 2009.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1345-1464

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 2009.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

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 2009.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-6903

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 Metabol. Pharmacokinet (Drug Metabolism and Pharmacokinetics) 24(6) ( 2 ) 167-174 - 174 2009.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

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 Metab Dispos (Drug metabolism and disposition: the biological fate of chemicals) 37 ( 5 ) 962-968 - 968 2009.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 0090-9556

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.

Br. J. Clin. Pharmacol (British Journal of Clinical Pharmacology) 67(1) ( 1 ) 44-49 - 49 2009.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 03065251

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.

Eur J Clin Pharmacol (European Journal of Clinical Pharmacology) 65 ( 7 ) 699-704 - 704 2009.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 00316970

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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Inhibitory effects of herbal extracts on the activity of human sulfotransferase isoform SULT1A3.

Nagai M, Fukamachi T, Tsujimoto M, Ogura K, Hiratsuka A, Ohtani H,Hori S, Sawada Y.

Biol. Pharm. Bull 32(1) 105-109 2009.01

Research paper (scientific journal), Joint Work, Accepted

Inhibitory effects of herbal extracts on the activity of human sulfotransferase isoform sulfotransferase 1A3 (SULT1A3)

Nagai M., Fukamachi T., Tsujimoto M., Ogura K., Hiratsuka A., Ohtani H., Hori S., Sawada Y.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 32 ( 1 ) 105 - 109 2009.01

ISSN 09186158

Sulfotransferase 1A3 (SULT1A3) is a phase II detoxifying enzyme of xenobiotics predominantly expressed in the intestinal epithelium. Recent increase in the use of herbal extracts as dietary supplements may lead to an increase in the possibility of dietary supplement-drug interactions. The purpose of the present study was to investigate the effects of 18 herbal extracts on SULT1A3 activity and the possibility of interaction between medicinal drugs and herbal extracts. We examined the inhibitory potencies of 18 herbal extracts on the sulfation of dopamine, a typical substrate of SULT1A3, and ritodrine, a β 2 stimulant, by human recombinant SULT1A3. The sulfation of dopamine was inhibited by extracts of banaba, green tea, Rafuma, grape seed, peanut seed coat, gingko biloba leaf, St. John's wort, gymnema and milkthistle. The IC 50 values of these herbal extracts were lower than the putative gastrointestinal concentration when the recommended dose was ingested. On the other hand, chlorella extract and rutin showed no inhibitory effects and wheat, mulberry and siberian ginseng had IC 50 values exceedingly higher than the putative gastrointestinal concentration. The inhibitory profiles of herbal extracts for the sulfation of ritodrine were comparable to those for the sulfation of dopamine. In conclusion, the extracts of herbs such as banaba and green tea potently inhibited SULT1A3 activity. These extracts may increase the bioavailability of drugs whose bioavailabilities were limited by the function of SULT1A3 on the intestinal epithelium. © 2009 Pharmaceutical Society of Japan.

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The first case of phenytoin intoxication associated with the concomitant use of phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium.

Tsuda A, Fujiyama J, Miki A, Hori S, Ohtani H, Sawada Y*.

Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology) 62(3) ( 3 ) 427-432 - 432 2008.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 03445704

Purpose: We reported the first case of phenytoin intoxication due to the concomitant use of phenytoin and TS-1, together with a review of the literature regarding the occurrence of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs such as fluorouracil (5-FU) and tegafur (FT). Methods: We showed the clinical course of our patient. Reports of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs in the English and Japanese language literature up to 2007 were identified by searching Medline and ICHUSHI Web (Japana Centra Revuo Medicina). Results: A patient taking phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium, experienced lightheadedness and repeated falls associated with an increase in serum phenytoin concentration (32.8 μg/ml) at 1 month after the start of TS-1 treatment. The time lag between initiation of combined treatment and onset of adverse symptoms suggests the presence of an indirect mechanism, rather than direct inhibition of drug-metabolizing enzymes by drugs in TS-1 or their active metabolites. Conclusions: Plasma phenytoin concentration should be closely monitored in patients receiving TS-1 and phenytoin concomitantly. © 2007 Springer-Verlag.

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Effects of uremic serum and uremic toxins on hepatic uptake of digoxin.

Tsujimoto M, Kinoshita Y, Hirata S, Otagiri M, Ohtani H, Sawada Y.

Ther. Drug Monit (Therapeutic Drug Monitoring) 30(5) ( 5 ) 576-582 - 582 2008.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 01634356

Not only the renal clearance but also the hepatic clearance of drugs varies with the progression of renal failure. The aim of this study was to investigate the effects of human uremic serum and various uremic toxins on the hepatic uptake of digoxin (DX), a drug mainly excreted into bile in patients with severe renal failure, using isolated rat and human hepatocytes as model systems. Uremic serum inhibited the uptake of DX into rat hepatocytes in a concentration-dependent manner, whereas normal serum did not affect the uptake. In addition, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol (PC) concentration dependently inhibited the uptake. CMPF and PC at the concentration of 400 μΜ, which is within the plasma concentration range attained in patients with renal failure, inhibited the uptake of DX into rat hepatocytes by 27% and 23%, respectively. In human hepatocytes, 10% uremic serum, 400 μΜ CMPF, and 400 μΜ PC inhibited the uptake of DX by 23.3%, 23.4%, and 28.2%, respectively. In conclusion, our results suggest that hepatic uptake of DX is likely to be inhibited by uremic toxins, such as CMPF and PC, present in the serum of patients with renal failure. Copyright © 2008 by Lippincott Williams & Wilkins.

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青汁をはじめとする健康食品の使用実態・意識調査.

朝比奈泰子, 本間秀彰, 堀里子, 大谷壽一, 三木晶子, 後藤輝明, 河野弘之, 澤田康文.

医療薬学 ((一社)日本医療薬学会) 34(7) ( 7 ) 644-650 - 650 2008.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

ドラッグストアを訪れた消費者を対象に、青汁を飲む動機、青汁の安全性と有効性についての認識、サプリメント一般に関する情報の必要性など青汁の使用実態をアンケート調査した。2006年2〜3月に北海道、東北、関東地方のツルハの調剤併設ドラッグストア68店を訪れた患者、消費者563名を調査対象とした。青汁服用者は65歳以上の高齢者、降圧薬、抗アレルギー薬、糖尿病治療薬の長期間服用者で有意に多かった。33.2%は効果があると考えていたが、55%はわからないと答えた。青汁服用による体調不良は2.4%で起った。その他、毎日服用(55.5%)、注意事項不読(27%)などであった。青汁服用は長期医薬品服用の高齢者に多いことが判明した。青汁服用の効果と副作用についての証拠を集め、消費者に注意事項が確実に伝わる方法を検討する必要がある。

Influence of SLCO1B3 gene polymorphism on the pharmacokinetics of digoxin in terminal renal failure.

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

Drug Metabol. Pharmacokinet (Drug Metabolism and Pharmacokinetics) 23(6) ( 6 ) 406-411 - 411 2008.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Digoxin (DX) is mainly excreted unchanged in the urine. In patients undergoing hemodialysis (HD patients), the relative contribution of hepatic elimination is increased. DX is a substrate of OATP1B3 (SLCO1B3), expressed on the sinusoidal membranes of hepatocytes in humans. Therefore, we investigated the relationship between SLCO1B3 gene polymorphisms and the value of trough concentration-to-dose ratio (C/D ratio) of DX in HD patients. We investigated two deletion polymorphisms in complete linkage disequilibrium (-28 to -11 and -7 to -4) and two SNPs in complete linkage disequilibrium (T334G and G699A). Blood was sampled 62-72 hours after the oral administration of DX. The C/D ratio of DX was lower in patients with the deletion allele than in those homozygous for the insertion allele, and was lower in patients with the 334T/669G allele than in those homozygous for the 334G/699A allele, although the differences were not statistically significant. The C/D ratio of DX was significantly higher in patients with homozygous for the insert-variant allele (median: 121.8 (ng/mL)/(mg/week/kg), range: 92.5-259.4 (ng/mL)/(mg/week/kg) than in others (median: 93.4 (ng/mL)/(mg/ week/kg), range: 66.5-154.3 (ng/mL)/(mg/week/kg)). In conclusion, the insert-variant allele of the OATP1B3 gene may increase the C/D ratio of DX in HD patients.

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患者を対象としたケトプロフェンテープの使用感に関する製剤間比較調査.

斉田翌美, 井上綾子, 石橋久, 冨永宏治, 堀里子, 三木晶子, 大谷壽一, 小野信昭, 澤田康文.

薬学雑誌 ((公社)日本薬学会) 128(5) ( 5 ) 795-803 - 803 2008.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-6903

46歳女性にKPテープ先発品Aを1日1回痛みに応じて、腰部と膝関節に貼付していたが、後発品Bに変更した後、使用感の相違が生じた。そこでA使用者39名(男6名、女33名、20〜86歳)とB使用者27名(男7名、女20名、39〜85歳)を対象に、テープ剤、外袋、ライナーについて調べ、テープ剤の評価を行い、貼付後の患部の状態についても調べた。先発品Aと後発品Bには使用感に差があり、先発品Aは後発品Bに比較し高く評価される傾向が認められた。先発品A使用経験を有する患者は使用経験がない患者に比べ、後発品Bに対する評価が低い傾向がみられた。貼付剤の使用感に関する比較試験は採用薬の選定や製剤切り替え時の服薬指導に有用である。

Genetic polymorphisms in the 5-hydroxytryptamine type 3B receptor gene and paroxetine-induced nausea.

Tanaka M, Kobayashi D, Murakami Y, Ozaki N, Suzuki T, Iwata N, Haraguchi K, Ieiri I, Kinukawa N, Hosoi M, Ohtani H, Sawada Y, Mine K*.

International Journal of Neuropsychopharmacology (International Journal of Neuropsychopharmacology) 11(2) ( 2 ) 261-267 - 267 2008.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 14611457

Selective serotonin reuptake inhibitor (SSRI)-induced nausea can be severe enough to lead to early treatment discontinuation. However, it is currently not possible to predict the occurrence of nausea before the initiation of SSRI treatment. In this study, we investigated the effect of genetic polymorphisms in the 5-hydroxytryptamine type 2A, 3A, and 3B (5-HT3B) receptors, 5-HT transporter, and CYP2D6 genes on the incidence of paroxetine-induced nausea. A consecutive series of 72 Japanese patients with depressive or anxiety disorders were treated with paroxetine. Paroxetine-induced nausea was assessed by a pharmacist and was observed in 29.2% of the patients. A significant (nominal p=0.00286) association was found between the incidence of nausea and the -100_-102AAG insertion/deletion polymorphism of the 5-HT3B receptor gene. No significant associations were observed between the other genetic polymorphisms and the incidence of nausea. The -100_-102AAG deletion variant of the 5-HT3B receptor gene may a.ect paroxetine-induced nausea. © 2007 Collegium Internationale Neuropsychopharmacologicum.

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クラリスロマイシンドライシロップと各種カルボシステイン製剤併用時の苦味強度における先発医薬品と後発医薬品間の違い.

松尾律子, 田中祥子, 加納美知子, 磯野喜美子, 田中泰羽, 田浦智子, 浅田由貴, 赤嶺有希子, 沢井一, 木下正和, 須藤智美, 久野木良子, 三木晶子, 堀里子, 佐藤宏樹, 大谷壽一, 澤田康文.

薬学雑誌 ((公社)日本薬学会) 128(3) ( 3 ) 479-485 - 485 2008.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-6903

クラリスロマイシンドライシロップ(CAM-DS)と、カルボシステイン(CC)製剤であるムコダインドライシロップ(MDS)及びムコダイン細粒(MGr)を同時処方した場合の苦味発現の程度について検討した。健康成人男性5名を対象に官能実験を行い、苦味強度を5段階評価した。先発品CAM-DSや、MDS,MGrはそれぞれ単独では苦味強度は低いが、CAM-DSをMDS,MGr又はMGr1(MGr後発品)と混合すると苦味強度が有意に増加した。先発品を含むCAM-DSの9製剤をMDSと混合したところ、後発品CDS7において苦味増加度が他剤と比較して有意に低かった。後発品を含むCCシロップは、先発品CAM-DSと混合した場合、CAM-DS+MDSより苦味強度が有意に低かった。

Bitterness of the mixture of clarithromycin dry syrup and carbocisteine preparation-difference between branded and generic drugs

Matsuo R., Tanaka S., Kanou M., Isono K., Tanaka Y., Taura T., Asada Y., Akamine Y., Sawai H., Kinosita M., Sudou T., Kunoki Y., Miki A., Hori S., Satoh H., Ohtani H., Sawada Y.

Yakugaku Zasshi (Yakugaku Zasshi) 128 ( 3 ) 479 - 485 2008.03

ISSN 00316903

The purpose of this study was to assess the bitterness intensity and pH of the solutions of clarithromycin dry syrup (CAM-DS), carbocisteine preparation (CC), and the concomitant use of both drugs. We conducted 6 types of human gustatory sensation tests with 6 healthy male volunteers. As a result, there was almost no difference in the bitterness intensity of CAM-DS between the branded (the latest and former preparations) and the generic formulations. The bitterness intensity of CAM-DS (the latest and former preparations of the branded as well as the generic formulations) was almost equally enhanced by mixing it with either the branded CC-DS or the branded and the generic carbocisteine granule (CC-Gr). On this occasion, the enhancing the bitterness of the branded CAM-DS (latest and former preparation) was nearly avoided safely by dosage form's changing CC-DS or CC-Gr to the branded CC-Sy. However, unlike the branded CC-Sy, some generic CC-Sy failed to suppress the bitterness. Furthermore, it was proven that some generic CAM-DS were shown to exhibit bitterness when mixed with even branded CC-Sy. In conclusion, it should be noted that the extent of bitterness of the mixture of CAM-DS and CC highly varies among the generic formulations. © 2008 The Pharmaceutical Society of Japan.

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Inhibitory effects of various beverages on human recombinant sulfotransferase isoforms SULT1A1 and SULT1A3.

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

Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition) 28(9) ( 9 ) 491-500 - 500 2007.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 01422782

Sulfotransferase (SULT) 1A1 and SULT1A3 play important roles in the presystemic inactivation of β2 agonists in the liver and intestine, respectively. The study aimed to investigate the inhibitory effects of grapefruit juice, orange juice, green tea, black tea and oolong tea and their constituents on the activities of SULT1A1 and SULT1A3. The activities of both SULT1A1 and SULT1A3 were significantly inhibited by all the beverages investigated at a concentration of 10%. The beverage constituents were tested in concentration ranges considered to be physiologically relevant. The grapefruit constituent, quercetin, completely inhibited SULT1A1, while quercetin and naringin both partially inhibited SULT1A3. The orange constituents, tangeretin and nobiletin, also completely inhibited SULT1A1. The tea constituents, (-)-epicatechin gallate and (-)-epigallocatechin gallate, both almost completely inhibited SULT1A1 and SULT1A3. Moreover, the theaflavin and thearubigin fractions of black tea both completely inhibited SULT1A1 and strongly inhibited SULT1A3. The inhibitory action of green tea on SULT1A3 was competitive, while that of black tea and oolong tea was mixed competitive/non-competitive. Mechanism-based inhibition was not observed with any beverage. In conclusion, various beverages, especially teas, inhibit the function of SULT1A3, and therefore may have the potential to increase the bioavailability of orally administered substrates of SULT1A3, such as β2 agonists. Copyright © 2007 John Wiley & Sons, Ltd.

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Relationship between MDR-1 polymorphism and brain penetration of fexofenadine, an antihistamine, evaluated by PET with [11C]doxepin

Tashiro M., Tsujimoto M., Kato M., Ohtani H., Itoh M., Sawada Y., Yanai K.

Journal of Cerebral Blood Flow and Metabolism (Journal of Cerebral Blood Flow and Metabolism) 27 ( SUPPL. 1 ) BP20 - 07 2007.11

ISSN 0271678X

Background and aims: Histamine H1 receptor (H1R) antagonists, or antihistamines, mainly act on the peripheral tissues but can induce sedation. This undesirable central side effect is caused by blockade of nerve transmission in the histaminergic neuron system. Variation in sedative properties of antihistamines is due to difference in their blood-brain barrier (BBB) permeability, partly defined by activity of P-glycoprotein (P-gp), an efflux pump located in the membrane of endothelial cells in brain capillaries. The aim of the present study is to evaluate the effects of single nucleotide polymorphisms (SNP) of the P-gp encoding "multi-drug resistance gene (MDR)-1" on BBB permeability of a non-sedative antihistamine, fexofenadine, that is a substrate of P-gp, using positron emission tomography (PET) with [11C]doxepin. Methods: Healthy young male volunteers (n=39, ranging 19-36 y.o.) were recruited and examined for genotyping of the common SNP in exon 26 (C3435T). Twenty-two out of the 39 subjects were studied by PET with [11C]doxepin following oral administration of placebo or fexofenadine 120 mg, in a single blind cross-over design. PET scan started 90 min following administration of each drug and the dynamic data, obtained taking 90 min, were analyzed based on Logan reference method to yield binding potential in various cortical structures. Based on the biding potential data of each subject in two drug conditions, histamine H1 receptor occupancy (H1RO) due to fexofenadine was calculated for each subject and the individual H1RO values were compared between wild-type (CC: n=6), heterozygous (CT: n=13) and homozygous (TT: n=3) subgroups. Results: Overall mean H1RO due to fexofenadine in the 22 subjects was calculated as -5%. The mean H1ROs of the 3 subgroups, CC, CT and TT, were -13.4, -3.7 and -1.4%, respectively, although the difference was not significant. Conclusions: The reason that H1RO of fexofenadine was calculated as lower than zero is not known. The PET results might suggest the presence of slight decrease in efflux function of P-glycoprotein in BBB among holders of C3435T mutation in comparison to wild-type in human. Further investigation is needed to draw a definitive conclusion with larger sample size, including studies on other mutations and other influx and efflux transporters. Functional and molecular imaging will be a strong tool for establishment of "individualized medicine".

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