Details of a Researcher - Ohtani, Hisakazu

Papers - Ohtani, Hisakazu

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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".

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 2007.10

Research paper (scientific journal), Joint Work, Accepted, 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 2007.10

Research paper (scientific journal), Joint Work, Accepted, 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 2007.09

Research paper (scientific journal), Joint Work, Accepted, 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 2007.08

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 2007.07

Research paper (scientific journal), Joint Work, Accepted, 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 2007.06

Research paper (scientific journal), Joint Work, Accepted, 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 2007.06

Research paper (scientific journal), Joint Work, Accepted, 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 2007.06

Research paper (scientific journal), Joint Work, Accepted, 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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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 Metabol Dispos (Drug Metabolism and Disposition) 35(5) ( 5 ) 772-778 - 778 2007.05

Research paper (scientific journal), Joint Work, Accepted, 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 2007.04

Research paper (scientific journal), Joint Work, Accepted

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 2007.04

Research paper (scientific journal), Joint Work, Accepted, 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 2007.04

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 2007.02

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 2007.02

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 2007.01

Research paper (scientific journal), Joint Work, Accepted

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 2007.01

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 2006.11

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