Published papers

This study aimed to characterize the inactivation kinetics of cytochrome P450 3A4 (CYP3A4) by erythromycin, which involves mechanism-based inhibition (MBI), in detail. In addition to an MBI assay based on the conventional method in which erythromycin and recombinant CYP3A4 were pre-incubated for 15 min, the study also evaluated the long-term MBI kinetics of this reaction by pre-incubation for 120 min. Mechanism-based inhibition profiles were obtained using three typical substrates, testosterone, midazolam and nifedipine. In the long-term assay, erythromycin evoked a time-dependent biphasic reduction in enzyme activity, but some residual activity (α) was detected in the terminal phase. The inactivation rate constant obtained in the presence of 30 μm erythromycin using nifedipine as a substrate was 1.44-fold higher than that acquired using testosterone, while there was no difference among the α values obtained with the three substrates. In the short-term assay, time-dependent monophasic inactivation was observed. To extrapolate these data to in vivo, the extent of the increase in the area under the curve (AUC ratio) induced by erythromycin was estimated from the results of the conventional short-term experiment and the long-term experiment examining residual activity. The AUC ratio estimated from the long-term kinetics (2.92) was closer to the clinically reported values (3.3–4.42). In conclusion, the relatively long-term evaluation of the kinetics of CYP3A4 inactivation revealed that the enzyme was not fully inactivated by erythromycin. To improve the estimation of the extent of the drug–drug interactions induced by MBI from in vitro data, longer-term investigations of the target enzyme's inactivation profile might be necessary.

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。

気管支喘息治療に適応をもつツロブテロールの全身作用型経皮吸収製剤であるホクナリンテープは、持続的な薬物放出制御システム(結晶レジンボアシステム)により、過度な血中濃度上昇を抑制することで全身性の副作用(振戦や心悸亢進など)を軽減し、さらに長時間作用を持続させることでモーニングディップ(早朝の喘息発作)を抑制することが示されている。ツロブテロール貼付剤にはホクナリンテープ以外にも複数の後発医薬品が承認されており、生物学的同等性試験により先発医薬品と同等であることが検証されている。しかし、後発医薬品では結晶レジンボアシステムは採用されておらず、ツロブテロールの放出がホクナリンに比べて速いことがin vitroの実験で示されている。臨床的にも、先発医薬品で喘息症状が良好にコントロールされていた患者が後発医薬品への切替え後に症状増悪した症例や副作用(振戦)が出現した症例が報告されている。そこで今回、先発医薬品から後発医薬品への切替えにより生じうる影響について検討するため薬物動態学的解析を行った。その結果、後発医薬品の血中移行性は皮膚透過性の影響を受けやすく、皮膚透過性が高まっている患者ではツロブテロールの副作用リスク増大や治療効果減弱をきたしうることが示唆された。

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

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

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。

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

Aim: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in full-term pregnant women leads to fetal or neonatal toxicity, such as constriction of the ductus arteriosus (DA) and persistent pulmonary hypertension in the newborn. The aim of this study was to predict quantitatively the fetal toxicity of three NSAIDs (antipyrine, salicylic acid and diclofenac) using the transplacental pharmacokinetic parameters obtained from our previous placental perfusion studies. Methods Human fetal plasma concentration profile after oral administration of each NSAID to the mother was estimated using the transplacental pharmacokinetic parameters and pharmacokinetic parameters in adult women. The fetal plasma concentration-response relationship for the three NSAIDs was estimated by pharmacokinetic/pharmacodynamic analysis of the results of previous studies investigating the effects of NSAIDs on the ratio of inner diameter of the DA to that of the pulmonary artery (DA/PA) in rats and the plasma concentration profiles of NSAIDs in pregnant rats. Results The risk of constriction of the DA was well predicted by the model. Mean DA/PA ratio after oral administration of diclofenac to the mother was estimated to be 39.0%, whereas both of the corresponding values after oral administration of antipyrine and salicylic acid were estimated to be 5.9%. These results suggest that the fetal risk of diclofenac is higher than those of salicylic acid and antipyrine. Conclusions This study presents a novel approach to predict quantitatively the fetal risk of NSAIDs administered to the mother. Human placental perfusion study and pharmacokinetic/pharmacodynamic analysis may provide basic data for predicting human fetal toxicity of drugs. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

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.

平成24年度薬局実務実習を終了した大学薬学部5年生を対象にアンケート調査を行い一般用医薬品(over-the-counter drug、OTC薬)実習改善のための方策について検討した。全体集計には回収分(158名、回収率94.6%)を使用し、記入漏れのない回答を有効回答とし、統計解析により有効回答(152名、有効回答率91.0%)のみを使用した。薬局OTC薬実習において27.8%(44名)の学生が来局者に対し、販売することができ、18.4%(29名)の学生が相談販売を行うことができた。相談販売を行った学生の中には指名販売を含めると50回以上販売できた学生が2名いた。一方で、販売、ロールプレイ(RP)、OTC薬販売の見学など、演習形式の実習のいずれも実施しない学生が11.4%(18名)いた。OTC薬実習に対する学生の「興味」「十分な実施」「満足度」に関しては実施状況による差がみられた。

Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the E(max) model with an 'effect compartment' could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation)induced by coadministration of DP and EM in rats.

Incadronate concentrates into the bone as a target organ after intravenous administration of incadronate disodium. Mature osteoclasts has take up incadronate from the bone surface and convert it from an active to an inactive form. As a result, incadronate decreases the plasma calcium concentration by suppressing bone resorption. In this study, the pharmacokinetic and pharmacodynamic (PK/PD) analysis model for ascertaining the anti-hypercalcemic effects of incadronate disodium was developed in rats. Data on both the concentration of incadronate in bone and that of free calcium in blood after intravenous administration from our previous study were used for analysis. To estimate the concentration in the surface layer of bone, data on the concentration of incadronate in bone after single intravenous administration were analyzed based on the PK model considering three-compartments. The estimated concentrations in the surface layer in bone were applied to the PD model as an input function. The PD model was developed to analyze the changes in the plasma calcium concentration after a single intravenous administration considering an irreversible inhibition of osteoclast activity. The obtained fitted curves were in good agreement with the observed data. The model could explain the long duration of the antihypercalcemic effect of incadronate disodium and should be useful for planning rational dose regimens for effective antihypercalcemic therapy.

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.

Background and purpose Internationalization of pharmacists, as well as pharmacy students, in terms of both the knowledge to care for international patients and to have medical information literacy, is a current concern in Japan. Educational activity and setting Keio University Faculty of Pharmacy has developed an elective course for pharmacy students, based on written agreements with the United States and Thailand that establish a student clinical rotation exchange program. The exchange program lasts for four to six weeks and involves clinical rotations in hospitals abroad during the students’ sixth year. Rotations follow a four-week didactic preparatory course. The course objectives are to acquire the knowledge, skills, and attitude needed to function as leading pharmacists with an international perspective. Methods We asked students to complete a feedback survey inquiring about the usefulness of preparatory courses, self-evaluation pre- and post-rotation satisfaction with the program, and overall self-assessment. Findings Twenty-four out of 41, i.e., 58.5% of the students replied with feedback. All respondents replied that the preparatory course was useful. They also replied that, based on their self-evaluation, they were satisfied with their level of English language skill improvement after the rotation. Pharmaceutical knowledge satisfaction, however, was slightly decreased. All respondents replied that this program was of a satisfactory nature, with 71%, 63%, and 92% of the respondents replying that they could acquire the knowledge, skills, and attitude program objectives respectively. Summary It is possible to successfully develop an overseas clinical rotation program. Students were quite satisfied upon completion and achieved the expected objectives.

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drag concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms · ml/μg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for malting a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

Background: Digoxin is distributed in skeletal muscles in high concentrations. The most reliable parameter to measure the distribution of digoxin in patients undergoing hemodialysis is not known. Objective: To estimate which distribution parameter-estimated lean body mass (E-LBM) calculated by subtracting the fat mass from the dry weight, lean body mass, dry weight, and ideal body weight - is the most reliable predictor for assessing the accuracy of a digoxin dosing regimen in patients undergoing hemodialysis. Methods: A retrospective study was conducted to evaluate 21 patients undergoing hemodialysis who were administered digoxin. The patients were divided into 2 groups: digoxin 0.125 mg administered twice a week (low-dose group) or 3 times per week (high-dose group). The differences between E-LBM, lean body mass, dry weight, and ideal body weight for the low- and high-dose groups were determined. The relationships between serum digoxin concentrations and the weekly digoxin dose per E-LBM, lean body mass, dry weight, and ideal body weight were also determined. Results: E-LBM, lean body mass, dry weight, and ideal body weight in the high-dose group were significantly larger than those in the low-dose group (p = 0.021, 0.015, 0.024, and 0.0029, respectively), although no significant difference in serum digoxin concentrations was evident. Significant correlation was found between serum digoxin concentrations and the weekly digoxin dosage per E-LBM, dry weight, lean body mass, and ideal body weight (r = 0.746, p < 0.0001; r = 0.638, p = 0.0014; r = 0.645, p < 0.0011; r = 0.553, p = 0.0083, respectively). Conclusions: E-LBM appears to reflect the best parameter for predicting serum digoxin concentrations. The use of the dry weight parameter could be generally useful for adjusting the dosage of digoxin in patients undergoing hemodialysis.

Among several classes of antidepressants, tricyclic antidepressants are known to prolong QTc intervals (QT interval corrected by heart rate) in electrocardiograms, while selective serotonin uptake inhibitors (SSRI) are considered to be devoid of arrhythmogenicity. In this study, we aimed to compare the arrhythmogenic potencies of imipramine (IMI), a typical tricyclic antidepressant, and fluvoxamine (FLV), an SSRI, at therapeutic and supratherapeutic concentrations using guinea pigs in vivo. Guinea pigs were anesthetized, and IMI (10 and 20 mg/kg/h) or FLV (20 mg/kg/h) was intravenously administered for 90 minutes to obtain the time-courses of drug concentrations in plasma and the changes in the QTc intervals during and after the drug administration. IMI induced distinct QTc prolongation in a dose-dependent manner, while FLV prolonged QTc intervals only slightly. A pharmacokinetic-pharmacodynamic analysis revealed that the potency for QTc prolongation of IMI was 1.7-fold higher than that of FLV. Taking the therapeutic concentration into account, the clinical risk of FLV for QTc prolongation was suggested to be 5-fold lower than that of IMI. Therefore, this SSRI agent was suggested to be safer than the tricyclic antidepressant for patients with cardiac risk factors, including arrhythmia, or for those taking other arrhythmogenic drugs concomitantly.

The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

The objectives were to investigate the ability of population-based in vitro-in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus. A population-based pharmacokinetic simulator (Simcyp) was used to simulate tacrolimus clearance from in vitro metabolism data and demographic characteristics of Japanese liver transplant patients (JLTs). The relationship between haematocrit and dose-to-concentration (D/C) ratio was validated using seven JLTs, whose highly variable haematocrit and D/C ratio were previously analysed. This validation was used as a surrogate for establishing 'interindividual' variability and to assess the power of clinical studies to discern the effect of haematocrit, sex and CYP3A5 genotype on tacrolimus clearance in a virtual JLT population. The relationship between haematocrit and D/C ratio was reproducible by Simcyp and corresponded well to those observed in seven JLTs. The number of JLTs required to detect the influence of CYP3A5 genotype and sex were estimated to be about 50 and > 600, respectively, which was consistent with the results of previous population pharmacokinetic studies for tacrolimus. In conclusion, population-based IVIVE is considered to be a useful approach to assess the influence of covariates a priori before conducting clinical studies. This is also helpful with study design and assessment of the statistical power of clinical studies involving population-based pharmacokinetics to detect the effects of covariates. Copyright © 2011 John Wiley & Sons, Ltd.