研究者詳細 - 大谷　壽一

論文 - 大谷　壽一

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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年01月

研究論文（学術雑誌）, 共著, 査読有り

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年01月

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年08月

研究論文（学術雑誌）, 共著, 査読有り, 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.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 30(5) （ 5 ） 576-582 - 582 2008年08月

研究論文（学術雑誌）, 共著, 査読有り, 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年07月

研究論文（学術雑誌）, 共著, 査読有り, 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 Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics） 23(6) （ 6 ） 406-411 - 411 2008年05月

研究論文（学術雑誌）, 共著, 査読有り, 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年05月

研究論文（学術雑誌）, 共著, 査読有り, 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年03月

研究論文（学術雑誌）, 共著, 査読有り, 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年03月

研究論文（学術雑誌）, 共著, 査読有り, 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年03月

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年12月

研究論文（学術雑誌）, 共著, 査読有り, 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 ） 2007年11月

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".

Effects of various methoxyflavones on vincristine uptake and multidrug resistance to vincristine in P-gp-overexpressing K562/ADM cells

Ohtani H., Ikegawa T., Honda Y., Kohyama N., Morimoto S., Shoyama Y., Juichi M., Naito M., Tsuruo T., Sawada Y.

Pharmaceutical Research （Pharmaceutical Research） 24(10) （ 10 ） 1936-1943 - 1943 2007年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07248741

Purpose. Some methoxyflavones (MFs) are known to inhibit the function of P-glycoprotein. The aim of this study is to characterize the reversal of multidrug resistance (MDR) by MFs. Methods. The effects of 19 MFs, including 3,5,6,7,8,3′,4′-heptamethoxyflavone, nobiletin, and tangeretin, and flavone on the uptake of [3H]vincristine into an adriamycin-resistant variant of human chronic myelogenous leukemia (K562/ADM) cells were investigated. Potentiation of vincristine-induced growth inhibition by these MFs was also tested in K562/ADM cells by means of WST-1 [2-(4-iodophenyl)-3-(4- nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] assay. Results. All MFs (20 μM) tested increased the uptake of [3H]vincristine. 3,5,6,7,8,3′,4′-heptamethoxyflavone, nobiletin, tangeretin, quercetagetin and quercetin pentamethylether showed especially potent effects. The increase in the uptake of [3H]vincristine was proportional to the number of methoxyl moieties. While substitution with a methoxyl moiety at the C3 position was the most influential, methoxyl substitution at both the C3′ and C5′ positions resulted in a decrease in the potentiation of uptake. Furthermore, there was a significant correlation between the potencies for increasing [3H]vincristine uptake and for growth inhibition assessed by WST-1 assay. Conclusions. MFs increased the uptake of [ 3H]vincristine into MDR cells and exhibited MDR-reversing effects. Their potencies were influenced by the number and positions of the methoxyl moieties. © 2007 Springer Science+Business Media, LLC.

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Possible case of potentiation of the antiplatelet effect of cilostazol by grapefruit juice

Taniguchi K., Ohtani H., Ikemoto T., Miki A., Hori S., Sawada Y.

Journal of Clinical Pharmacy and Therapeutics （Journal of Clinical Pharmacy and Therapeutics） 32(5) （ 5 ） 457-459 - 459 2007年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 02694727

We present a case of purpura associated with concomitant ingestion of cilostazol, aspirin and grapefruit juice. A 79-year-old man with atherosclerosis obliterans, taking cilostazol and aspirin, complained of purpura. Interview by a pharmacist revealed that he had been taking grapefruit juice for a month. His purpura disappeared upon cessation of grapefruit juice, although his medication was not altered. The most probable cause of his purpura is an increase in the blood level of cilostazol because of the inhibition of cilostazol metabolism by components of grapefruit juice. Aspirin may possibly have potentiated the risk of purpura. Grapefruit juice should be avoided in patients taking cilostazol, especially in patients being concomitantly treated with other anticoagulants. © 2007 The Authors.

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後発医薬品の使用に伴い生じたインシデント・アクシデント事例の実態とその解析.

堀里子, 寺門千佳子, 石河利恒, 大和田邦明, 宇野幹子, 三木晶子, 大谷壽一, 天野武城, 澤田康文*.

医薬品情報学（(一社)日本医薬品情報学会） 9(3) （ 3 ） 205-209 - 209 2007年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1345-1464

東京23区及び多摩地区の医療機関、保険調剤薬局に後発医薬品に関するアンケート用紙を配布し、臨床において後発医薬品が関係して生じたトラブルの事例を収集し、その要因を分析した。アンケートの総回答数は1148件(回収率64.9%)であった。後発医薬品が関係したインシデント・アクシデント事例として87例を収集した。医薬品の取り違えは49件と最も多く、その多くは薬名が類似しているものであった。次いで、先発医薬品と後発医薬品の適応症の違いが11件、使用感・服用感の違いが9件などであった。後発医薬品への切り替えに伴う効果の増強・減弱や有害事象の発生に関する訴えが5件収集されたが、これらの事象と後発医薬品への切り替えとの因果関係は不明である。

健康食品に関する使用実態調査研究の統合により見いだされた諸問題解決のための提案

朝比奈泰子, 堀里子, 大谷壽一, 佐倉統, 澤田康文

医薬品情報学（(一社)日本医薬品情報学会） 9 （ 2 ） 150 - 157 2007年08月

ISSN 1345-1464

国民の健康食品への意識、使用動向を明らかにし、健康食品の安心・安全を確保するための方法を提案することを目的として、健康食品の使用実態や消費者・医療従事者の健康食品に関する意識を国内で調査・解析した過去の報告を収集し、統合を行った。十分な回答者数があり(N=300以上)、調査対象及び調査方法が明らかな9件のアンケート調査を選定し、使用目的、医療従事者と消費者との情報共有、情報の入手先と使用のきっかけ、健康食品の購入と入手先、健康被害の経験に関するデータを抽出し、解析した。その結果、健康食品に関して、健康被害をはじめとする多くの情報が見落とされ、また消費者がテレビやインターネット等で発信される不確かな情報を参考に健康食品を使用している可能性があるという現状が明らかになった。これらの結果を踏まえ、健康食品の安心・安全を確保するための全国ネットワークを提案した。

Effects of dosing interval on the pharmacokinetic interaction between oral small spherical activated charcoal and amlodipine in humans

Tanaka C., Ohtani H., Tsujimoto M., Ohdo S., Taniguchi M., Mizooku Y., Saitoh Y., Kimura M., Uchimaru H., Irie S., Sawada Y.

Journal of Clinical Pharmacology （Journal of Clinical Pharmacology） 47(7) （ 7 ） 904-908 - 908 2007年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00912700

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Piloerection induced by replacing fluvoxamine with milnacipran

Hori S., Matsuo N., Yamamoto A., Hazui T., Yagi H., Nakano M., Suzuki Y., Miki A., Ohtani H., Sawada Y.

British Journal of Clinical Pharmacology （British Journal of Clinical Pharmacology） 63(6) （ 6 ） 665-671 - 671 2007年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03065251

Aims: To present a case of piloerection after replacing fluvoxamine maleate with milnacipran hydrochloride, and to analyse this effect based on receptor occupancy theory. Methods: A 40-year-old female with a 3-year history of panic disorder was prescribed fluvoxamine 50 mg day-1 in addition to clorazepate dipotassium and sulpiride. Depression was not improved and she complained of fatigue, lack of energy and drowsiness. These symptoms worsened within a few days of an increase in the dose of fluvoxamine to 50 mg twice daily. Since an interaction between fluvoxamine and tizanidine, prescribed by another clinic, was suspected, fluvoxamine was replaced with milnacipran 50 mg day-1. Although her drowsiness improved, she complained of piloerection throughout her body. This symptom gradually abated within a week and when the dosage of milnacipran was increased to 100 mg day-1 at 2 months, no further piloerection occurred. We calculated the changes in α1-adrenoceptor occupancy by endogenous norepinephrine during treatment with the usual doses of milnacipran, fluvoxamine and imipramine by using pharmacokinetic and pharmacodynamic parameters obtained from the literature. Results: The ratios of α1-adrenoceptor occupancy by endogenous norepinephrine during the treatment with milnacipran, fluvoxamine and imipramine to that without drug were estimated to be 7.13, 1.00 and 4.12, respectively. The α1-adrenoceptor occupancy by endogenous norepinephrine was increased in a dose-dependent manner by milnacipran, whereas fluvoxamine had essentially no effect. Conclusions: The piloerection observed after the replacement of fluvoxamine with milnacipran in this patient appears to have been due to an increase in the α1-adrenoceptor occupancy by endogenous norepinephrine induced by milnacipran. © 2007 The Authors.

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Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats

Yamasaki D., Tsujimoto M., Ohdo S., Ohtani H., Sawada Y.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 22(3) （ 4 ） 162-168 - 411 2007年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01634356

The plasma concentration of phenytoin (PHT) is decreased by coadministration of folinate (leucovorin; LV), a folate (FA) analogue. The aim of this study was to examine the effect of LV on the pharmacokinetics of PHT in rats in vivo and to investigate the mechanism of the interaction. LV (50 mg/kg) was administered orally to rats concomitantly given intravenous PHT (50 mg/kg) to evaluate the effect of LV on the pharmacokinetics of PHT. The effect of LV on the plasma protein binding of PHT was investigated by using plasma from rats that had received oral LV. We also examined the effects of LV on the uptake of PHT into isolated rat hepatocytes and on the metabolism of PHT in isolated rat hepatocytes and rat hepatic microsomes. LV significantly increased the systemic clearance (2-fold) and liver-to-blood partition coefficient (1.24-fold) of PHT. However, it did not affect the plasma protein binding or hepatic uptake of PHT. LV increased the metabolism of PHT in isolated rat hepatocytes, with a significant 1.41-fold increase in the maximum rate of metabolism and a decrease in the Michaelis-Menten constant. On the other hand, 5-methyltetrahydrofolate (5-MTHF), a primary metabolite of LV and FA, significantly increased p-hydroxylation of PHT in rat hepatic microsomes, whereas LV and FA themselves had no effect. In conclusion, these results suggest that, in rats, LV, an FA analogue, decreases the plasma concentration of PHT by increasing the hepatic metabolism of PHT, and the increase in the PHT metabolism is, at least in part, attributable to 5-MTHF. © 2007 Lippincott Williams & Wilkins, Inc.

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Development of a pharmacokinetic model to optimize the dosage regimen of TS-1, a combination preparation of tegafur, gimeracil and oteracil potassium.

Inoue S., Ohtani H., Tsujimoto M., Hori S., Sawada Y.

Drug metabolism and pharmacokinetics （Drug metabolism and pharmacokinetics） 22(3) （ 3 ） 162-168 - 168 2007年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

BACKGROUND: TS-1 is a combination preparation of tegafur, a prodrug of 5-fluorouracil (5-FU), with gimeracil, a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), which mediates the inactivation of 5-FU. UFT is a combination preparation of tegafur with uracil, which also inhibits DPD, though less potently; UFT has a higher content of tegafur than that in TS-1. We aimed to develop a pharmacokinetic model to describe the kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. METHODS: We developed a model incorporating the inhibition of DPD by gimeracil and uracil, and fitted the model to the observed kinetics of tegafur and 5-FU after the administration of TS-1 and UFT. Then, we simulated the plasma 5-FU profiles in patients with renal dysfunction and those after replacement of TS-1 with UFT and compared them with the observed profiles. RESULTS: The developed model could appropriately describe the plasma concentration profiles of 5-FU and tegafur after the administration of TS-1 in patients with normal and impaired renal function. CONCLUSION: The developed model may be useful to optimize the dosage regimen of TS-1 under various clinical conditions.

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