研究者詳細 - 秋好　健志

論文 - 秋好　健志

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Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage.

Tsuchitani T, Akiyoshi T, Imaoka A, Ohtani H

Journal of pharmaceutical health care and sciences （Journal of Pharmaceutical Health Care and Sciences） 7 （ 1 ） 24 2021年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2055-0294

Background: Irinotecan (CPT-11) is clinically known to cause severe diarrhea and gastrointestinal damage. Recently, we have reported that CPT-11-induced gastrointestinal damage is associated with the upregulation of intestinal P-glycoprotein (P-gp) expression and decreased absorption of its substrate, dabigatran etexilate (DABE), using a rat model. However, the P-gp activity or its contribution to the decreased absorption remains unclear. The aim of this study was to quantitatively evaluate how P-gp activity changes in rats with CPT-11-induced gastrointestinal damage, as assessed by the absorption of digoxin (DGX), a typical P-gp substrate. Methods: Male Sprague-Dawley rats were intravenously administered CPT-11 at a dose of 60 mg/kg/day for 4 days to induce gastrointestinal damage. Then, the rats were administered DGX orally (40 μg/kg), after some of them were orally administered clarithromycin (CAM; 10 mg/kg), a P-gp inhibitor. DGX (30 μg/kg) was administered intravenously to determine the bioavailability (BA). The rats’ DGX plasma concentration profiles were determined using LC-MS/MS. Results: CPT-11 treatment decreased the maximum concentration (Cmax) and area under the plasma concentration-time curve (AUCpo) of DGX, which does not contradict to the DABE study. Although in the CPT-11-treated group the BA of DGX was significantly decreased to 40% of the control value, CAM did not affect the BA of DGX in the CPT-11-treated group. Conclusions: Increased P-gp expression in rats with CPT-11-induced gastrointestinal damage is not necessarily associated with increased P-gp activity or contribution to the drug absorption in vivo. The decreased DGX absorption observed in this study might be attributable to other factors, such as a reduction in the absorptive surface area of the gastrointestinal tract.

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Estimation of absolute oral bioavailability without performing an intravenous clinical study.

Ohtani H, Iwata R, Imaoka A, Akiyoshi T

Drug metabolism and pharmacokinetics （Drug Metabolism and Pharmacokinetics） 38 100392 2021年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1347-4367

The absolute oral bioavailability (BA) of drugs are yet to be determined, and intravenous pharmacokinetic studies are currently considered indispensable for determining the BA values of oral drugs. The aim of this study was to develop and validate a novel approach to estimating BA values without intravenous pharmacokinetic data. Based on the drug inclusion criteria, such as exhibiting a urinary recovery rate of (R<inf>u</inf>) of ≥20% in a clinical study, 13 drugs were included in the present study, and pharmacokinetic data for them were collected from the literature. The fraction excreted unchanged into urine (f<inf>e</inf>) was calculated for healthy subjects by dividing the R<inf>u</inf> value by the total recovery rate. The contribution of renal excretion to total clearance from the systemic circulation (R<inf>ren</inf>) was estimated by subjecting oral clearance and creatinine clearance to regression in subjects with normal and impaired renal function. BA was estimated as f<inf>e</inf>/R<inf>ren</inf> and compared with the observed BA (BA<inf>obs</inf>). The predicted BA values for 9 drugs fell within ±20% of their BA<inf>obs</inf>. The examined approach makes it possible to estimate BA values for drugs with mean renal excretion values in healthy subjects and oral clearance in subjects with various renal function, without intravenous pharmacokinetic data.

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Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants.

Yamaguchi Y, Akiyoshi T, Kawamura G, Imaoka A, Miyazaki M, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H

Drug metabolism and pharmacokinetics （Drug Metabolism and Pharmacokinetics） 38 100384 2021年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1347-4367

Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals inhibit CYP3A4 to cause clinically significant drug-drug interactions. In the present quantitative study, we investigated the inhibitory effects of three azole antifungals (ketoconazole, voriconazole, and fluconazole) on testosterone metabolism by recombinant CYP3A4 genetic variants (CYP3A4.1 (WT), CYP3A4.2, CYP3A4.7, CYP3A4.16, and CYP3A4.18) and compared them with those previously reported for itraconazole. The inhibition constants (K ) of ketoconazole, voriconazole, and fluconazole for rCYP3A4.1 were 3.6 nM, 3.2 μM, and 16.1 μM, respectively. The K values of these azoles for rCYP3A4.16 were 13.9-, 13.6-, and 6.2-fold higher than those for rCYP3A4.1, respectively, whereas the K value of itraconazole for rCYP3A4.16 was 0.54-fold of that for rCYP3A4.1. The other genetic variants had similar effects on the K values of the three azoles, whereas a very different pattern was seen for itraconazole. In conclusion, itraconazole has unique characteristics that are distinct from those shared by the other azole anti-fungal drugs ketoconazole, voriconazole, and fluconazole with regard to the influence of genetic variations on the inhibition of CYP3A4. i i i i

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Exacerbation of atrioventricular block associated with concomitant use of amlodipine and aprepitant in a lung cancer patient: A case report.

Hibino H, Makino Y, Sakiyama N, Makihara-Ando R, Hashimoto H, Akiyoshi T, Imaoka A, Fujiwara Y, Ohe Y, Yamaguchi M, Ohtani H

International journal of clinical pharmacology and therapeutics （International Journal of Clinical Pharmacology and Therapeutics） 59 （ 4 ） 328 - 332 2020年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0946-1965

Objective: To report a case of second-degree atrioventricular block associated with concomitant use of aprepitant and amlodipine. Case: A 73-year-old man with lung cancer was treated with aprepitant for prophylactic use for the prevention of nausea and vomiting, concomitantly with cisplatin, gemcitabine, and an investigational drug (anti-epidermal growth factor receptor monoclonal antibody). He was diagnosed with first-degree atrioventricular block and was taking amlodipine for hypertension. During the first cycle of chemotherapy, 5 days after the start of aprepitant, he experienced Wenckebach second-degree atrioventricular block (Mobitz type I), and amlodipine was discontinued. After day 6, the atrioventricular block was not shown. According to the Naranjo adverse drug reaction scale, a score of 7 was obtained (causality: probable). In addition, using the Drug Interaction Probability Scale, a score of 6 was obtained (causality: probable). Conclusion: The drug-drug interaction between aprepitant and amlodipine was considered to have deteriorated his atrioventricular block, conceivably due to the inhibition of cytochrome P450 (CYP) 3A-mediated metabolism of amlodipine by aprepitant.

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Citrus Fruit-Derived Flavanone Glycoside Narirutin is a Novel Potent Inhibitor of Organic Anion-Transporting Polypeptides.

Morita T, Akiyoshi T, Sato R, Uekusa Y, Katayama K, Yajima K, Imaoka A, Sugimoto Y, Kiuchi F, Ohtani H

Journal of agricultural and food chemistry （Journal of Agricultural and Food Chemistry） 68 （ 48 ） 14182 - 14191 2020年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-8561

Organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1 are expressed in the small intestine and are involved in drug absorption. We identified narirutin, which is present in grapefruit juice, as a novel OATP inhibitor. The citrus fruit jabara also contains high levels of narirutin; therefore, we investigated the inhibitory potency of jabara juice against OATPs. The inhibitory effects of various related compounds on the transport activity of OATPs were evaluated using OATP-expressing HEK293 cells. The IC50 values of narirutin for OATP1A2- and OATP2B1-mediated transport were 22.6 and 18.2 μM, respectively. Other flavanone derivatives from grapefruit juice also inhibited OATP1A2/OATP2B1-mediated transport (order of inhibitory potency: naringenin > narirutin > naringin). Five percent jabara juice significantly inhibited OATP1A2- and OATP2B1-mediated transport by 67 ± 11 and 81 ± 5.5%, respectively (p < 0.05). Based on their inhibitory potency and levels in grapefruit juice, the inhibition of OATPs by grapefruit juice is attributable to both naringin and narirutin. Citrus × jabara, which contains narirutin, potently inhibits OATP-mediated transport.

Relative contributions of metabolic enzymes to systemic elimination can be estimated from clinical DDI studies: Validation using an in silico approach.

Koinuma K, Tsuchitani T, Imaoka A, Akiyoshi T, Ohtani H

International journal of clinical pharmacology and therapeutics （International Journal of Clinical Pharmacology and Therapeutics） In press （ 3 ） 231 - 238 2020年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0946-1965

Objective: The contribution ratios (CR) of metabolic enzymes to the systemic clearance of a drug can be estimated from in vitro studies. Another feasible approach is to calculate them based on the increase in the area under the time-concentration curve (AUC) caused by the co-administration of a potent and selective inhibitor in a clinical drug-drug interaction (DDI) study. However, some factors, such as the inhibitory potency of the inhibitor and the inhibition of first-pass metabolism, might affect the estimation of CR based on clinical DDI studies. We aimed to validate the accuracy of the DDI-based estimation of CR using an in silico approach. Materials and methods: An in silico DDI study was conducted using a population-based physiological pharmacokinetic simulator to estimate the CR of cytochrome P450 (CYP)3A4 for zolpidem, sildenafil, omeprazole, triazolam, and repaglinide. The ratio of the AUC value seen in the presence of an inhibitor (ketoconazole or itraconazole) to that observed in the absence of the inhibitor (AUC ratio) was also calculated. The CR for CYP3A4 obtained using the simulator (CR ) were compared with those calculated from the AUC ratio (CR ). Results: When ketoconazole was used, good correlations between the CR and CR were obtained for all examined substrates (inconsistencies were seen in < 10% of subjects). CR estimates derived from the AUC ratio were found to be accurate. Some underestimation was observed, possibly due to incomplete inhibition, and some overestimation caused by extensive first-pass metabolism was noted. Conclusion: This study verified that CR obtained from AUC ratios in DDI studies are quite reliable. def est est def

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Novel method to estimate the appropriate dosing interval for activated charcoal to avoid interaction with other drugs.

Ohtani H, Nakamura K, Imaoka A, Akiyoshi T

European journal of clinical pharmacology （European Journal of Clinical Pharmacology） 76 （ 11 ） 1529 - 1536 2020年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0031-6970

© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Activated charcoal is known to adsorb a variety of drugs concomitantly administered and reduce their intestinal absorption, and separating the dosing is considered a practical approach to avoid this drug interaction. The aim of the present study was to develop and validate a simple method to estimate the sufficient dosing interval to avoid drug interaction using the pharmacokinetic profile of the subject drugs administered alone and the amplitude of interaction upon simultaneous administration with activated charcoal. Methods: For each subject drug, the pharmacokinetic profile and the amplitude of interaction, as assessed by AUCR (the ratio of area under the plasma concentration-time curve (AUC) in the presence of activated charcoal to that in its absence), were collected from previous reports. The AUCR value was estimated based on the compartment model under the assumption that the subject drug in the first gastrointestinal compartment is immediately adsorbed to a certain extent upon the administration of activated charcoal. The estimated AUCR (AUCRe) for each drug with certain dosing interval was compared with the respective AUCR value reported previously (AUCRobs). Results: Among twenty concentration profiles for 14 subject drugs obtained from previous reports, 15 AUCRe values fell in the range of 80–120% of the respective AUCRobs values. Conclusion: The developed method enabled estimation of the amplitude of DDI by activated charcoal administered in a certain dosing interval, whereas overestimation of AUCRe was observed for drugs that undergo extensive enterohepatic circulation.

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Profile of the inhibitory effects of gefitinib on CYP2D6 variants in vitro.

Semba Y, Akiyoshi T, Hibino H, Imaoka A, Ohtani H

International journal of clinical pharmacology and therapeutics （International journal of clinical pharmacology and therapeutics） 58 （ 10 ） 539 - 542 2020年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0946-1965

OBJECTIVE: CYP2D6 is a highly polymorphic metabolic enzyme with more than 100 genetic variants, some of which are associated with significantly altered enzyme activity, such as CYP2D6.2 (Arg296Cys, Ser486Thr), CYP2D6.10 (Pro34Ser, Ser486Thr), and CYP2D6.39 (Ser486Thr). Gefitinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) and is used to treat non-small-cell lung cancer with EGFR mutations. Gefitinib is known to competitively inhibit CYP2D6 activity. The aim of this study was to quantitatively compare the inhibitory effects of gefitinib on CYP2D6 enzyme kinetics among CYP2D6 variants. MATERIALS AND METHODS: The enzymatic activity of several CYP2D6 genetic variants; i.e., CYP2D6.1 (wild type), CYP2D6.2, CYP2D6.10, and CYP2D6.39, was assessed by examining the O-demethylation of dextromethorphan. RESULTS AND CONCLUSION: The intrinsic clearance of dextromethorphan (Vmax/Km) for CYP2D6.2, CYP2D6.10, and CYP2D6.39 were 0.565-, 0.0376-, and 0.470-fold of that for wild type, respectively. For all variants, the mixed inhibition model was better at explaining the nature of the inhibitory effects of gefitinib than the competitive inhibition model. However, the inhibitory potency of gefitinib varied among the CYP2D6 genetic variants. The Ki values for CYP2D6.2, CYP2D6.10, and CYP2D6.39 were 1.4-, 2.5- and 1.5-fold higher than that for wild type, respectively, implying that these variants are less susceptible to the inhibition by gefitinib. The genetic variations in CYP2D6 might be one of the factors responsible for inter-individual differences in the strength of CYP2D6-mediated drug interactions involving gefitinib.

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pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2.

Morita T, Akiyoshi T, Sato R, Katayama K, Yajima K, Kataoka H, Imaoka A, Sugimoto Y, Ohtani H

Drug metabolism and pharmacokinetics （Drug Metabolism and Pharmacokinetics） 35 （ 2 ） 220 - 227 2020年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1347-4367

© 2019 The Japanese Society for the Study of Xenobiotics Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS. In the present study, we evaluated the influence of pH on the OATP1A2-mediated uptake of estrone 3-sulfate using OATP1A2-expressing HEK293 cells. The uptake of 0.3 μM estrone 3-sulfate by HEK293-OATP1A2 cells was pH-dependent. OATP1A2 exhibited bimodal saturation kinetics at pH 6.3 and 7.4. Compared with that seen at pH 6.3 (5.62 μM), the Km value of the high-affinity site was 8-fold higher at pH 7.4 (43.2 μM). In addition, the influence of pH on the potency of inhibitors varied among the examined inhibitors. These results suggest that the transport properties of OATP1A2 under lower pH conditions, such as those found in the microenvironments of the small intestinal mucosa and distal tubules, differ from those seen under neutral pH conditions.

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医薬品の第三者への転売・譲渡の違法性に関する消費者の意識調査.

大谷壽一, 藤井萌未, 今岡鮎子, 望月真弓, 山浦克典, 秋好健志.

医薬品情報学（(一社)日本医薬品情報学会） 22 （ 1 ） 30 - 34 2020年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1345-1464

医薬品をインターネットオークションに出品することや第三者に譲渡することの違法性を一般消費者がどれくらい認識しているか調査した。処方箋の調剤待ち時間を利用して来局した20歳以上の患者またはその家族にアンケートの概要を説明し、151件の有効回答を得た。28.5%の患者が医薬品を他人から譲り受けた経験を有していることが明らかとなった。薬局で購入した湿布薬を他人から譲り受けるかインターネットオークションで買うことに対する違法性の認識はそれぞれ9.9%、24.5%と低く、転売や譲渡が必ずしも違法とはならない化粧品や健康食品の譲渡に対する違法性の認識とほぼ同程度であった。「違法である」との認識は睡眠薬が最も高く、ついで風邪薬、湿布薬の順であった。病院で処方された湿布薬を「インターネットオークションで買うこと」について違法性の認識は60代未満または女性で有意に高かった。

Irinotecan-induced gastrointestinal damage impairs the absorption of dabigatran etexilate.

Hattori T, Imaoka A, Akiyoshi T, Ohtani H

Biopharmaceutics & drug disposition （Biopharmaceutics and Drug Disposition） 40 （ 9 ） 315 - 324 2019年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0142-2782

© 2019 John Wiley & Sons, Ltd. Irinotecan causes serious gastrointestinal damage. Dabigatran etexilate (DABE), an oral anticoagulant and substrate of P-glycoprotein (P-gp), is poorly absorbed and exhibits low bioavailability in humans. The aim of this study was to evaluate the effects of irinotecan-induced gastrointestinal damage on the pharmacokinetics/pharmacodynamics (PK/PD) of DABE. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. To investigate the PK profile of dabigatran (DAB), an active moiety of DABE, DABE was administered orally on day 5, and then DAB was administered intravenously on day 6. To evaluate the PD profile of DAB, the activated partial thromboplastin time (APTT) was measured. The protein expression level of intestinal P-gp was evaluated. In the irinotecan-treated rats, the area under the concentration–time curve of DAB after the oral administration of DABE and the bioavailability of DABE were decreased significantly. The APTT ratio also decreased, suggesting that the impaired efficacy of DABE was attributable to a reduction in its bioavailability. The expression of intestinal P-gp was higher in the irinotecan-treated rats. Taking into consideration the histological damage caused to the intestinal epithelium, both the increased P-gp expression and the reduced passive diffusion were considered to be responsible for the reduction in the bioavailability of DABE.

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インターネットオークションにおける無承認無許可医薬品の出品実態.

大谷壽一*, 藤井萌未, 今岡鮎子, 秋好健志.

医療薬学（(一社)日本医療薬学会） 45 （ 10 ） 591 - 595 2019年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

インターネットオークションサイト「ヤフオク!」における無承認無許可医薬品の取引実態調査を行うことで、一般消費者に対する医薬品の適正使用啓蒙活動に必要な基礎的情報を構築することを目的とした。調査は第1回を平成28年6月13日〜平成28年6月17日、第2回を平成28年7月28日〜平成28年7月31日の期間内にそれぞれ実施した。第1回調査ではキーワードにより3758件の商品が検索され、そのなかから571件の違法商品と48件のグレー商品が確認された。第2回調査では3808件の商品が検索され、そのうち581件の違法商品と40件のグレー商品が確認された。違法商品のうち入札のあった商品は第1回目の調査では19件(3.3%)、第2回目の調査では24件(4.1%)であった。製造国は第1回調査では日本が423件(74.1%)、外国が146件(25.6%)、第2回調査では日本が446件(76.8%)、外国が134件(23.1%)であり、少なからず外国製の商品も見出された。

Inhibitory kinetics of fruit components on CYP2C19 activity

Seki H, Akiyoshi T, Imaoka A, Ohtani H.

Drug Metabol Pharmacokinet （Drug Metabolism and Pharmacokinetics） 34 （ 3 ） 181 - 186 2019年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

© 2019 The Japanese Society for the Study of Xenobiotics It has been suggested that the fruit components resveratrol (RSV), 6′, 7′-dihydroxybergamottin (DHB), and bergamottin (BG) might inhibit cytochrome P450 2C19 (CYP2C19) activity, but the mode and potency of such inhibition are yet to be investigated. This study aimed to investigate the mode and kinetics of the inhibition of CYP2C19-based omeprazole metabolism by RSV or grapefruit juice components (DHB or BG). RSV and DHB reduced CYP2C19 activity in a preincubation time-dependent manner, suggesting that they inactivated CYP2C19 via mechanism-based inhibition (MBI). Although BG inactivated CYP2C19 in a preincubation time- and concentration-dependent manner, suggesting that both MBI and reversible inhibition contributed to these effects, the concentration required to achieve 50% inhibition was 26-fold higher for reversible inhibition than for MBI (0.859 and 0.0331 μM, respectively), indicating that the inhibition of CYP2C19 by BG is primarily attributable to MBI. Based on the estimated intestinal concentrations of these components, it is considered that >90% of CYP2C19 would be inactivated after the consumption of normal amounts of grapefruit juice or RSV-containing substances. In conclusion, these findings suggest that food containing these components has the potential to evoke drug-food interactions caused by the MBI of intestinal CYP2C19 activity in the clinical setting.

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Effects of food type on the extent of drug-drug interactions between activated charcoal and phenobarbital in rats

Ogata Y., Imaoka A., Akiyoshi T., Ohtani H.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics） 34 （ 4 ） 287 - 291 2019年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

© 2019 Activated charcoal is known to decrease the intestinal absorption of co-administered drug by adsorption. The extent of this drug-drug interaction (DDI) is attenuated by food intake. The aim of this study was to quantitatively evaluate the effects of food type on the extent of DDI between phenobarbital and activated charcoal using a rat model. Phenobarbital was orally administered at a dose of 1.5 mg/kg with or without 33 mg/kg of activated charcoal under fasted or fed conditions, and the plasma concentration profile of phenobarbital was monitored. Several fed conditions, such as a standard breakfast, high-fat meal or enteral nutrient used in human studies, were examined. Under the fasted conditions, activated charcoal significantly decreased the area under the plasma concentration - time curve (AUC) of phenobarbital by 45.2%. When the standard breakfast or high-fat meal was fed, this DDI was reduced to 28.3 and 18.0%, respectively, as assessed by the reduction in the AUC. On the contrary, enteral nutrient did not significantly attenuate the DDI. In conclusion, the influence of food intake on the extent of DDI between phenobarbital and activated charcoal was found to differ among the types of food concomitantly ingested.

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5-Fluororacil-Induced Gastrointestinal Damage Impairs the Absorption and Anticoagulant Effects of Dabigatran Etexilate.

Tsujii K, Hattori T, Imaoka A, Akiyoshi T, Ohtani H

Journal of pharmaceutical sciences （Journal of Pharmaceutical Sciences） 107 （ 5 ） 1430 - 1433 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00223549

© 2018 American Pharmacists Association® Fluoropyrimidines, including 5-fluororacil (5-FU), cause gastrointestinal damage in the clinical setting and might affect the gastrointestinal absorption of concomitantly administered drugs. We aimed to evaluate the effects of fluoropyrimidine-induced gastrointestinal damage on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DABE), an anticoagulant, in rats with gastrointestinal damage induced by the repeated oral administration of 5-FU. Rats were administered DABE orally or dabigatran (DAB), an active moiety of DABE, intravenously. The plasma DAB concentration was determined using liquid chromatography-tandem mass spectrometry. The activated partial thromboplastin time (APTT) was measured before and 30 min after the administration of each drug, and the APTT ratio was calculated. In 5-FU-treated rats, the maximum plasma concentration, the area under the concentration-time curve of DAB after the oral administration of DABE, and the oral bioavailability of DABE were significantly decreased to 18.3%, 22.9%, and 16.3% of the respective control values. The 5-FU-treated rats’ APTT ratio was also significantly lower than the control value. Fluoropyrimidine-induced gastrointestinal damage might reduce the plasma concentration of DAB by impairing DABE absorption and might attenuate the anticoagulant effects of DABE in the clinical setting.

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Food intake attenuates the drug interaction between new quinolones and aluminum.

Imaoka A, Abiru K, Akiyoshi T, Ohtani H

Journal of pharmaceutical health care and sciences （Journal of Pharmaceutical Health Care and Sciences） 14 （ 1 ） 4 - 11 2018年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2055-0294

© 2018 The Author(s). Background: Intestinal absorption of new quinolones is decreased by oral administration of polyvalent metal cations. Some clinical studies have demonstrated this drug - drug interaction is more prominent under fasted condition. However, the effect of food intake on the extent of drug - drug interaction between new quinolones and metal cations remains to be investigated quantitatively and systematically. The aim of this study was to develop an animal model that enables to evaluate the effect of food intake on the extent of drug - drug interaction in the gastrointestinal tract by chelation and to apply the model to evaluate quantitatively the effect of food intake on the drug - drug interaction between two new quinolones, ofloxacin or ciprofloxacin and sucralfate. Methods: The rats were orally administered new quinolones (5.3 mg/kg of ofloxacin or 10 mg/kg of ciprofloxacin) with or without 13.3 mg/kg of sucralfate under fasted or fed condition and plasma concentration profiles of new quinolones were monitored. To the fed group, standard breakfast used in human studies was pasted and administered at a dose of 8.8 g/kg. Results: The area under the plasma concentration - time curves (AUC0-6) of ofloxacin and ciprofloxacin under the fasted condition were significantly decreased to 28.8 and 17.1% by co-administration of sucralfate, respectively. On the contrary, sucralfate moderately decreased the AUC0-6 of ofloxacin and ciprofloxacin to 54.9 and 33.2%, respectively, under fed condition. The effects of sucralfate and food intake on the kinetics of ofloxacin in this study were well consistent with the results of previous clinical trial. Conclusions: The developed animal model quantitatively reproduced the effect of food intake on the drug - drug interaction between ofloxacin and sucralfate. The similar influences were observed for the drug - drug interaction between ciprofloxacin and sucralfate, suggesting that the extent of drug - drug interaction caused by chelation is generally attenuated by food intake.

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The extent of drug-drug interaction between amlodipine and activated charcoal is attenuated by food intake in rats

Imaoka A, Seki K, Akiyoshi T, Ohtani H.

Drug Metabol Pharmacokinet （Drug Metabolism and Pharmacokinetics） 34 （ 1 ） 108 - 110 2018年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

© 2018 Activated charcoal decreases gastrointestinal absorption of concomitantly administered drugs. The absorption of amlodipine (AML) was reported as almost completely attenuated by 25 g of activated charcoal under a fasted condition, but not affected by 2 g of activated charcoal under a fed condition. However, it is not clear whether this difference resulted from the food intake or the dose of activated charcoal. The aim of this study was to quantitatively evaluate the effect of food intake on drug interactions caused by adsorption to activated charcoal in the gastrointestinal tract in rats. The rats were orally administered 0.08 mg/kg of AML, with or without 33 mg/kg of activated charcoal, under the fasted or fed condition and the plasma concentration profiles of AML were monitored. For the fed group, the standard breakfast used in clinical studies was smashed and administered at a dose of 11 g/kg. The AUC value of AML under the fasted condition was significantly decreased to 24.8% by coadministration of activated charcoal. On the other hand, activated charcoal moderately decreased the AUC value of AML to 74.8% under the fed condition. These results suggest that the extent of drug interactions caused by activated charcoal is attenuated by food intake.

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5-Fluorouracil treatment alters the expression of intestinal transporters in rats.

Yotsumoto K, Akiyoshi T, Wada N, Imaoka A, Ohtani H

Biopharmaceutics & drug disposition （Biopharmaceutics and Drug Disposition） 38 （ 8 ） 509 - 516 2017年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0142-2782

Copyright © 2017 John Wiley & Sons, Ltd. 5-Fluorouracil (5-FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. This study aimed to investigate quantitatively the effect of 5-FU-induced intestinal damage on the expression of intestinal transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5-FU (30 mg/kg/day, p.o.) for 5 days to induce intestinal damage, and then the upper, middle and lower intestinal segments were removed. The mRNA and protein expression levels of these transporters in each segment were determined using quantitative real-time PCR and Western blotting, respectively. In the 5-FU-treated rats, the protein levels of P-gp and Bcrp in the upper segment were significantly increased to 15- and 2.6-fold of the control, respectively, while those in other segments were unaffected. Pept1 expression was increased by 5-FU in almost all segments. A remarkable increase in P-gp expression was shown, the uptake of digoxin, a P-gp substrate, in each intestinal segment was measured using a rat everted sac. As a result, the uptake of digoxin in the upper segments of 5-FU-treated rats was decreased compared with that of the control. In conclusion, 5-FU-induced intestinal damage was shown to alter the expression of these transporters, especially in the upper intestinal segment, while the characteristics of the influence varied among the transporters. The 5-FU-induced intestinal damage may affect transporter-mediated drug absorption of orally administered drugs in the clinical setting.

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Development and evaluation of an overseas clinical rotation program for undergraduate pharmacy students in Japan.

Ohtani H, Mitsui R, Akiyoshi T, Imaoka A, Abe Y, Kanke M, Nakamura N, Foster P, Mochizuki M

Currents in pharmacy teaching & learning （Currents in Pharmacy Teaching and Learning） 9 （ 3 ） 452 - 459 2017年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1877-1297

© 2017 Elsevier Inc. 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.

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Inactivation kinetics and residual activity of CYP3A4 after treatment with erythromycin.

Ishikawa Y, Akiyoshi T, Imaoka A, Ohtani H.

Biopharmaceutics & drug disposition （Biopharmaceutics and Drug Disposition） 38 （ 7 ） 420 - 425 2017年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0142-2782

Copyright © 2017 John Wiley & Sons, Ltd. 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.

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