研究等業績 - 原著論文 - 赤嶺 由美子
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Hayato Yokota, Yumiko Akamine, Harumi Hatakeyama, Hideaki Kagaya, Sho Sakamoto, Mitsuru Saito, Masahide Takeda, Kazuhiro Sato, Katsutoshi Nakayama, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences ( Journal of Pharmaceutical Health Care and Sciences ) 11 ( 1 ) 20 - 20 2025年03月
研究論文（学術雑誌）
BACKGROUND: Azole antifungals are the standard treatment for pulmonary mycosis, which may develop during long-term immunotherapy for kidney transplant. Isavuconazole (ISCZ) is a cytochrome P450 (CYP) 3 A inhibitor that has a risk of interacting with the immunosuppressive drug tacrolimus (TAC). We report a case of simple pulmonary aspergilloma with renal dysfunction due to increased trough levels of TAC after ISCZ coadministration. CASE PRESENTATION: A male in his 60s was treated with TAC 3.0 mg/day orally to prevent graft rejection after kidney transplantation. He received a loading dose of ISCZ 600 mg/day orally for two days, followed by a maintenance dose of 200 mg/day for simple pulmonary aspergilloma. The TAC trough concentration increased markedly from 2.4 to 9.9 ng/mL on day 6 after coadministration. The creatinine level increased from 0.70 to 1.08 mg/dL, suggesting renal dysfunction due to TAC. Subsequently, the TAC dosage was reduced, leading to a decreased blood TAC concentration and improved renal function. The patient's genotype was CYP3A5*1/*3. CONCLUSIONS: In the early stages of ISCZ treatment, the blood TAC concentration is higher, and CYP3A5 polymorphisms may partially explain the extent of this interaction. We recommend more careful monitoring of TAC and serum creatinine levels for approximately one week after ISCZ administration.
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Hayato Yokota, Kazuhiro Sato, Sho Sakamoto, Yuji Okuda, Masahide Takeda, Yumiko Akamine, Katsutoshi Nakayama, Masatomo Miura
Cancer chemotherapy and pharmacology ( Cancer Chemotherapy and Pharmacology ) 95 ( 1 ) 49 - 49 2025年03月
研究論文（学術雑誌）
PURPOSE: The inflammatory cytokine interleukin (IL)-6 reduces the activity of drug metabolic enzymes and promotes tumor progression. We investigated the effect of IL-6 on the pharmacokinetics of osimertinib and the association between an IL-6 polymorphism and clinical outcomes in 30 patients with non-small cell lung cancer (NSCLC). METHODS: Osimertinib and IL-6 plasma concentrations were measured on day 15 after therapy initiation. The genotype of IL-6 1800796G > C was identified using polymerase chain reaction-restriction fragment length polymorphism. Risk factors affecting overall survival (OS) were assessed by Cox proportional hazard regression analysis. RESULTS: The IL-6 concentration was significantly correlated with the osimertinib trough plasma concentration (r = 0.423, P = 0.020) and area under the plasma concentration-time curve (r = 0.420, P = 0.021). The IL-6 concentration was significantly higher in patients with the IL-6 rs1800796G allele versus C/C genotype (P = 0.024). OS was significantly shorter in patients with the IL-6 rs1800796G allele versus C/C genotype (median: 15.1 vs. 48.9 months, P = 0.005). Univariate and multivariate analyses indicated that the IL-6 rs1800796G allele is an independent risk factor for OS (crude hazard ratio = 7.07; P = 0.014; adjusted hazard ratio = 6.38; P = 0.021). CONCLUSION: A higher IL-6 concentration was associated with reduced metabolic activity of osimertinib, leading to increased osimertinib exposure. As the IL-6 concentration was higher in NSCLC patients with the IL-6 rs1800796G allele, it might be an independent prognostic factor for patients treated with osimertinib.
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Takahiro Kobayashi, Honami Sato, Yumiko Akamine, Yayoi Fukushi, Naoto Takahashi, Masatomo Miura
Xenobiotica; the fate of foreign compounds in biological systems ( Xenobiotica ) 55 ( 1 ) 1 - 6 2024年12月
研究論文（学術雑誌）
The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.
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Hayato Yokota, Yumiko Akamine, Mizuki Kobayashi, Takuro Kitabayashi, Misato Horie, Tentaro Endo, Takechiyo Yamada, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences ( Journal of Pharmaceutical Health Care and Sciences ) 10 ( 1 ) 2024年08月
研究論文（学術雑誌）
BACKGROUND: Naldemedine is an orally available peripherally acting μ-opioid receptor antagonist approved to treat opioid-induced constipation (OIC). It is contraindicated for patients with known or suspected gastrointestinal obstruction to protect against naldemedine-induced perforation. Here, we report a clinical case of suspected perforation of a diverticulum in the sigmoid colon associated with naldemedine. CASE PRESENTATION: The patient was a 65-year-old man with a history of oral cancer who had been prescribed oxycodone (20 mg/day) for cancer pain. On day 0, the patient started naldemedine 0.2 mg once daily before bedtime for OIC. The dose of oxycodone was increased for pain control up to 60 mg/day. On day 35 of naldemedine treatment, the patient developed fever and abdominal pain, and his frequency of defecation had decreased. Initial laboratory results showed a C-reactive protein (CRP) level of 28.5 mg/dL and white blood cell (WBC) count of 13,500/µL. On day 37, the patient still had tenderness in his lower abdomen. Abdominal computed tomography revealed free air in the abdominal cavity suggesting an intestinal perforation. A Hartmann procedure was performed. Histopathological findings showed numerous diverticula in the sigmoid colon, some of which were perforated. CONCLUSIONS: These results suggest that the effects of OIC may have compressed the intestinal tract, which was followed by naldemedine-activation of peristalsis, which led to the onset of intestinal perforation. In patients with pre-existing diverticular disease, we should monitor for increased WBC counts and CRP levels after the initiation of treatment with naldemedine, and consider performing appropriate tests early in the event of abdominal complaints.
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Kazuma Fujita, Yumiko Akamine, Haruka Igarashi, Yayoi Fukushi, Katsuya Sasaki, Koji Fukuda, Masafumi Kikuchi, Hiroyuki Shibata
Japanese journal of clinical oncology ( Japanese Journal of Clinical Oncology ) 54 ( 11 ) 1165 - 1170 2024年06月
研究論文（学術雑誌）
BACKGROUND: The modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) are indicators of nutritional status in cancer patients; however, the effects of baseline mGPS and PNI on the duration of administration of the ghrelin receptor agonist anamorelin, which is used to treat cachexia in patients with cancer, are unclear. This study aimed to clarify the association of mGPS and PNI with the duration of oral anamorelin administration for patients who did not have beneficial effects from anamorelin. METHODS: The attending physician determined the duration of oral anamorelin administration based on discontinuation due to cancer progression, poor efficacy, adverse events, or death. RESULTS: The 12-week continuation rate of oral anamorelin was 30.4%. Univariate analysis revealed that an Eastern Cooperative Oncology Group performance status (ECOG-PS) of ≥2 (P < .001), concurrent chemotherapy (P = .002), albumin level (P = .005), C-reactive protein level (P = .013), and a mGPS of 2 (P = .014) were statistically significant predictors of the 12-week continuation rate of oral anamorelin. In the multivariate analysis, a mGPS of 2 remained a significant risk factor, and the ECOG-PS and concurrent chemotherapy had no effect on the association between the mGPS and 12-week continuation rate of oral anamorelin. CONCLUSION: Patients with a mGPS of 2, compared with mGPS of 0 or 1, are less likely to maintain oral anamorelin therapy, regardless of the ECOG-PS or concurrent chemotherapy. Therefore, it is necessary to consider initiating anamorelin administration at mGPS 0 or 1.
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Hayato Yokota, Ruriko Asahi, Yumiko Akamine, Mizuki Kobayashi, Hiyu Wakabayashi, Sho Sakamoto, Yuji Okuda, Kazuhiro Sato, Katsutoshi Nakayama, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences ( Journal of Pharmaceutical Health Care and Sciences ) 10 ( 1 ) 2024年06月
研究論文（学術雑誌）
BACKGROUND: Anamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer. CASE PRESENTATION: A female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child-Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided. CONCLUSIONS: When administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring.
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Yumiko Akamine, Miyuki Matsushita, Satoru Morikawa, Masatomo Miura
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan ( 公益社団法人 日本薬学会 ) 143 ( 4 ) 377 - 383 2023年
研究論文（学術雑誌）
Plasma concentrations of mycophenolic acid (MPA), an immunosuppressive agent, have been measured in clinical settings using immunoassay methods or HPLC. However, immunoassay methods show cross-reactivity with metabolites of MPA glucuronide. Recently, the LM1010 high-performance liquid chromatography instrument was approved as a new general medical device. In this study, we compared the results of MPA plasma concentrations analyzed using the LM1010 method and the previously described HPLC method. Plasma samples obtained from 100 renal transplant patients (32 women and 68 men) were evaluated using both HPLC instruments. Deming regression analyses showed a very high correlation between the two instruments, with a slope of 0.9892 and an intercept of 0.0235 µg/mL (r2=0.982). Bland-Altman analysis showed an average of -0.0012 µg/mL between the LM1010 method and the previously described HPLC method. For the LM1010 method, the total run time for MPA analysis was 7 min, and the analytical time was short; however, the extraction recovery when using a spin column was extremely low for frozen plasma samples stored at -20°C for 1 month, and the volume required for the assay (150 µL) could not be collected. Thus, for the LM1010 method, analysis using fresh plasma samples was optimal. Overall, our findings showed that the LM1010 method was a rapid, accurate HPLC assay for MPA analysis and could be used in clinical practice for routine monitoring of MPA in fresh plasma samples.
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Yayoi Fukushi, Yumiko Akamine, Miyuki Matsushita, Satoru Morikawa, Masatomo Miura
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan ( 公益社団法人 日本薬学会 ) 143 ( 11 ) 963 - 969 2023年
研究論文（学術雑誌）
LM1010 HPLC is an emerging automated method designed for use in clinical settings. The aim of this study was to compare the analytical performance of LM1010 with the performance of traditional HPLC and LC-MS/MS in the measurement of plasma concentrations of imatinib. Seventy-eight plasma samples from 20 patients (14 men and 6 women) were collected. Plasma concentrations of imatinib in samples from the same patient were analyzed simultaneously using LM1010, HPLC and LC-MS/MS (LSI Medience Corporation). Strong correlations were seen in pairwise comparisons of results from the LM1010 and HPLC methods, the LM1010 and LC-MS/MS methods, and the LC-MS/MS and HPLC methods (Spearman's r=0.936, 0.906, and 0.953, respectively); however, the results from the LC-MS/MS method showed a positive proportional bias in comparison with the results from the LM1010 and HPLC methods, according to Deming analyses (slope=1.064 and 1.105, respectively). In Bland-Altman analyses, the LC-MS/MS method showed a positive mean bias of 98.6 and 112 ng/mL in comparison with the LM1010 and HPLC methods, respectively. Notably, results obtained using the LM1010 method were comparable to those using the HPLC method (positive mean bias=13.6 ng/mL; 95% confidence interval, -7.9-35.1 ng/mL). Biochemical parameters or drugs taken concomitantly with imatinib were not found to affect the bias of the LM1010 method. The LM1010 method can be applied to routine therapeutic drug monitoring of imatinib.
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Yayoi Fukushi, Yumiko Akamine, Maiko Abumiya, Nagi Tozawa, Takaya Yamashita, Miho Nara, Yoshihiro Kameoka, Naoto Takahashi, Masatomo Miura
British journal of clinical pharmacology ( British Journal of Clinical Pharmacology ) 89 ( 5 ) 1695 - 1700 2022年12月
研究論文（学術雑誌）
The effects of polymorphisms of ABCB1 and ABCG2 on the dose-adjusted plasma trough concentrations and cerebrospinal fluid (CSF)-to-plasma ratios of ponatinib were evaluated. Blood (C4 ) and CSF (CSF4 ) concentrations at 4 h after administration were determined. The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in subjects homozygous for ABCB1 variants 1236T/T, 2677T/T + T/A or 3435T/T were significantly higher than that in a group of subjects with other genotypes (P = .026, .012 and .015, respectively). The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in 4 patients with the combination of ABCB1 variants 1236T/T-2677T/T + T/A-3435T/T was 2.62% (1.42-3.42%); this ratio was significantly higher than that in subjects with other genotypes (1.08% [0.89-1.47%]; P = .006). The brain distribution of ponatinib was affected by ABCB1 polymorphisms and therefore seems to be modulated by P-glycoprotein at the blood-brain and blood-CSF barriers.
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Natsuki Fukuda, Takahiro Kobayashi, Honami Sato, Yumiko Akamine, Naoto Takahashi, Masatomo Miura
Journal of Chromatographic Science ( Oxford University Press (OUP) ) 62 ( 1 ) 58 - 64 2022年10月
研究論文（学術雑誌）
Abstract
A simple, highly sensitive and specific method based on high-performance liquid chromatography (HPLC) with ultraviolet detection was developed for the measurement of venetoclax concentrations in plasma samples. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH2PO4 (pH 3.5) (80/20, v/v) on a CAPCELL PAK C18 UG120 column at a flow rate of 0.5 mL/min. The quantitative method was validated based on standards described in “Bioanalytical Method Validation: Guidance for Industry” published by the US Food and Drug Administration. The separation of venetoclax and the internal standard R051012 was satisfactory, and the chromatograms were free of interfering peaks from the biological matrix. The intra- and inter-day coefficients of variation for venetoclax assays were &lt;12.9%, whereas intra- and inter-day accuracies were within 13.6%. Only 100 μL of human plasma was required to detect a lower limit of quantification of 10 ng/mL for venetoclax. The recoveries of venetoclax extracted with an Oasis HLB cartridge were between 81 and 85%. The developed HPLC method was successfully applied to the determination of venetoclax concentrations in plasma of acute myeloid leukemia patients taking venetoclax. The degree of drug interactions between venetoclax and CYP3A4 inhibitors can be determined by this HPLC assay. -
Fukuda N.
Cancer Chemotherapy and Pharmacology ( Cancer Chemotherapy and Pharmacology ) 89 ( 5 ) 609 - 616 2022年05月
研究論文（学術雑誌）
PURPOSE: We evaluated the plasma exposure and response relationships of nilotinib for patients with newly diagnosed chronic myeloid leukemia (CML) in real-world practice. METHODS: For the 26 patients enrolled in this study, at 3, 6, 12, and 24 months after nilotinib administration, the trough plasma concentrations (Ctrough) of nilotinib were analyzed. The relationships between nilotinib Ctrough and the molecular response to nilotinib treatment at each point (each n = 26) were evaluated. RESULTS: Median nilotinib Ctrough values were significantly higher in patients with a major molecular response (MMR) at 3 months than in patients without an MMR (809 and 420 ng/mL, respectively; P = 0.046). Based on the area under the receiver-operating characteristic curve, the threshold value of the nilotinib Ctrough at 3 months for predicting MMR achievement was 619 ng/mL at the best sensitivity (71.4%) and specificity (77.8%). Patients with a nilotinib Ctrough of above 619 ng/mL had a significantly shorter time to achievement of a deep molecular response (DMR; 9.0 and 18.0 months, respectively; P = 0.020) and higher rates of DMR by 2 years in Kaplan-Meier plots (P = 0.025) compared with that in patients with a nilotinib Ctrough of less than 619 ng/mL. CONCLUSION: For patients with newly diagnosed CML, the nilotinib dose may be adjusted using a Ctrough of above 619 ng/mL as the minimum effective concentration, i.e., the lowest concentration required for MMR or DMR achievement within a shorter time, during early stages after beginning therapy to obtain faster and deeper clinical responses.
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MAHO KUMAGAI, MITSUJI NAGAHAMA, YUMIKO AKAMINE, TOMOKO OZEKI, AKIFUMI SUZUKI, KIMINORI SUGINO, KOICHI ITO, MASATOMO MIURA
Cancer Diagnosis & Prognosis ( Anticancer Research USA Inc. ) 2 ( 3 ) 336 - 344 2022年05月
研究論文（学術雑誌）
Background/Aim: The purpose of this study was to investigate the relationships between the plasma concentration of Lenvatinib (C0), the levels of angiopoietin (Ang)-1 and Ang-2, and clinical responses to lenvatinib therapy in patients with thyroid cancer. Patients and Methods: Lenvatinib C0 and Ang were measured by high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. Results: The median decrease rates of Ang-1 and Ang-2 at 1 month after treatment from baseline were –15.3% and –48.4%, respectively. However, the decrease in the levels of Ang-1 and Ang-2 at 1 month from baseline did not correlate with C0. In patients with partial response (PR) and stable disease, Ang-2 at 1 month was significantly lower than Ang-2 at baseline. The area under the ROC for PR prediction was 0.667, giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of decrease rate of Ang-2 of –49.83%. Conclusion: The decrease in Ang-2 at 1 month of treatment from baseline may be important as a biomarker of the inhibitory effect of lenvatinib on angiogenesis.
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カペシタビン併用によるワルファリンの抗凝固能への影響とその時期に関する検討
齋藤 豪, 赤嶺 由美子, 三浦 昌朋, 平泉 達哉
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 57 ( 1 ) 79 - 85 2021年01月
研究論文（学術雑誌）
カペシタビンはCYP2C9に対する阻害作用を有するため、その基質であるワルファリンとの併用で、その血中濃度を上昇させ、プロトロンビン時間国際標準比(prothrombin time-international normalized ratio:以下、PT-INR)を上昇させることが知られている。しかしながら実際にPT-INRがどの程度上昇するのか、また相互作用が起こる時期について検討した報告は少ない。そこで我々は、カペシタビン併用によるワルファリンの抗凝固能に及ぼす影響と影響時期について検討した。対象患者7名のPT-INRの平均値は併用前1.86から併用後4.73と約2.5倍に上昇した(p=0.010)。ワルファリンが減量・中止されるまでの期間は8.0〜43.0日であった。ワルファリンの抗凝固能亢進はカペシタビン併用後1ヵ月以内に発現する可能性が高く、併用開始1ヵ月間はPT-INRを毎週測定しワルファリンの用量を調節していくことが重要であると考える。(著者抄録)
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 6 ) 1800 - 1803 2021年
研究論文（学術雑誌）
What is known and objective: We aim to add to the few reports on tacrolimus concentrations in breast milk and in maternal, umbilical vein and neonatal blood after maternal renal transplantation. Case summary: In a 30-year-old pregnant woman, the tacrolimus concentration at delivery was the same in maternal, umbilical vein and neonatal blood. The breast milk/maternal blood tacrolimus ratio ranged from 0.40 to 0.64. What is new and conclusion: The maternal and neonatal blood tacrolimus concentrations at birth are equivalent; thus, one must assume that maternal tacrolimus concentrations directly affect the foetus and/or neonate. Tacrolimus is not detectable in the neonate 3 weeks after birth, suggesting that there is minimal transfer through breast milk.
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 5 ) 1312 - 1318 2021年
研究論文（学術雑誌）
What is known and objective: The schizophrenia guidelines in Japan and many other countries describe clozapine as the first-choice drug for patients with treatment-resistant schizophrenia. However, there have been no reports to date on the effects of the introduction of clozapine on the prescription of other antipsychotics and concomitant drugs. Methods: In this study, we retrospectively investigated the prescription of antipsychotics and concomitant drugs before vs 6 months after and 12 months after switching to clozapine. Results and discussion: Clozapine was introduced to 62 patients with treatment-resistant schizophrenia, and 51 patients continued on clozapine therapy. Six months after switching to clozapine, there was a significant decrease in the mean number of antipsychotic drugs (2.04 ± 0.75 vs 1.10 ± 0.30: p < 0.001) and in the mean chlorpromazine equivalent value (1024 ± 73 mg/day vs 781 ± 391 mg/day: p < 0.001) compared to before switching. Moreover, antipsychotic monotherapy increased from 24% to 90% after switching to clozapine. In addition, the number of concomitant benzodiazepines, anti-parkinson drugs and antidepressants also significantly decreased 6 and 12 months after switching to clozapine (p < 0.001 for benzodiazepines and anti-parkinson drugs, and p < 0.05 for antidepressants). What is new and conclusion: Our study suggests that switching to clozapine may reduce the use of antipsychotic combination therapy, and may also reduce the number of concomitant drugs.
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Sakamoto S.
Investigational New Drugs ( Investigational New Drugs ) 38 ( 6 ) 1687 - 1695 2020年12月
研究論文（学術雑誌）
ATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled in this study. They were treated with gefitinib at a dose of 250 mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2 weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels and the area under the curve (AUC) values for 24-h gefitinib concentrations. We also compared these parameters among four groups distinguished according to the presence or absence of the polymorphism and PPI use. The mean trough gefitinib level and AUC value for 24-h gefitinib concentration were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 vs. 454.5 ng/mL, respectively, P = 0.021; AUC: 9949.9 vs. 13,085.4 ng・h/mL, respectively, P = 0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 vs. 340.5 ng/mL, respectively, P = 0.033). The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentrations.
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加藤 駿介, 赤嶺 由美子, 石川 誠, 三浦 昌朋
医薬品相互作用研究 ( (一社)医薬品相互作用研究会 ) 44 ( 3 ) 153 - 158 2020年12月
研究論文（学術雑誌）
術前3ヵ月以上前から睡眠薬を定期内服していた白内障手術患者28名(男性12名、女性16例、平均年齢69±13歳)を対象として、術後の睡眠薬処方状況を後方視的に調査し、白内障術後の睡眠薬の適正使用について検討した。術後に処方された睡眠薬のジアゼパム換算値の増減を評価した。その結果、ジアゼパム換算値は年齢や併用薬剤にかかわらず、術後1ヵ月以降より減少し、術後6ヵ月の時点で有意な減少が確認された。臨床検査値や併用薬剤数、副腎皮質ステロイド内服患者のヒドロコルチゾン換算値は睡眠薬処方の変化に影響を及ぼす有意な要因ではなかった。本研究より、白内障手術患者においては術後6ヵ月以降に睡眠薬を減薬できる可能性が示唆されたが、減薬・休薬のタイミングは難しく、患者の睡眠状況を確認し、長期的なモニタリングを経て減薬を提案することが望ましい。
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インドメタシンが未熟児動脈管開存症患者の尿量へ及ぼす影響と血清電解質の変化
大久保 翔, 赤嶺 由美子, 安達 裕行, 高橋 勉, 三浦 昌朋
医薬品相互作用研究 ( (一社)医薬品相互作用研究会 ) 44 ( 2 ) 96 - 101 2020年09月
研究論文（学術雑誌）
インドメタシン(IND)が未熟児の尿量へ与える影響、尿量減少の発生時期とその経過、IND投与後の血清電解質の変化を後方視的に検討した。在胎37週未満の早産児のうち、動脈管開存症(PDA)と診断された患者でINDを投与した24名をIND群、PDAと診断されたが早急なIND投与の必要性はないと判断され経過観察となった13名を対照群とした。IND群の尿量変化率の中央値は-38.5%であったのに対して、対照群は-10.0%と有意にIND群で尿量減少がみられた。水分率が90mL/kg/day未満に調整されている患者はIND群では24名中18名、対照群は13名中5名に認められており、IND群で有意に多くみられた。また、IND群では血清ナトリウム(Na)値が基準値以下まで低下したのは24名中11名、対照群では13名中1名とIND群で有意に多かった。血清カリウム値が基準値以上になったのはIND群で1名のみであった。IND投与が尿量へ与える影響は大きく、INDによる尿量減少は高い確率で投与後24時間以内に発生し、さらに希釈性の低Na血症を引き起こしていた。
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Sato S.
Pharmacological Reports ( Pharmacological Reports ) 72 ( 3 ) 622 - 630 2020年06月
研究論文（学術雑誌）
Background: The purpose of this study was to evaluate the effects of concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) cholesterol by the mammalian target of rapamycin (mTOR) inhibitor everolimus and their effects on genetic polymorphisms in the PCSK9 and mTORC1 genes in 53 renal transplant recipients. Methods: Prior to and on day 15 after everolimus administration, the concentrations of everolimus in blood and PCSK9 and LDL cholesterol in plasma were evaluated. Additionally, mTORC1 (rs2536T>C and rs2295080T>G) and PCSK9 (rs505151G>A, rs562556G>A, and rs11593680C>T) polymorphisms were analyzed. Results: Mean PCSK9 plasma concentrations on day 15 after everolimus treatment were significantly higher than those before treatment (295 versus 214 ng/mL, respectively; p = 0.004). Significant correlations between the area under the blood concentration–time curves (AUC)0–12 on day 15 of everolimus treatment and the change rate in PCSK9 concentrations were found (r = 0.316, p = 0.021). However, there were no significant correlations between the change rate in PCSK9 and LDL cholesterol concentrations. The change rate in PCSK9 concentrations by everolimus treatment was significantly greater in patients with the mTORC1 rs2295080G allele than the T/T genotype (p = 0.006); however, there were no significant differences between PCSK9 rs505151G>A and rs11583680C>T genotypes. In multivariate analyses, patients with mTORC1 rs2295080G (p = 0.010), higher everolimus AUC0–12 (p = 0.006), and female sex (p = 0.029) showed higher change rates of PCSK9 following everolimus therapy. Conclusions: Administration of everolimus significantly elevated plasma PCSK9 concentrations, potentially causing everolimus-induced hyperlipidemia.
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Ohkubo S.
Journal of Chromatographic Science ( Journal of Chromatographic Science ) 58 ( 10 ) 915 - 921 2020年
研究論文（学術雑誌）
Abstract
Here, we developed a novel high-performance liquid chromatography (HPLC) method for quantification of perampanel in clinical practice and investigated the relationships between the plasma concentrations of perampanel obtained by this HPLC method and the CYP3A4*1G polymorphism. The developed HPLC method was validated based on US Food and Drug Administration. The developed HPLC method could be performed with a plasma volume of only 200 μL and had a limit of quantification (LOQ) of 2.5 ng/mL. The coefficients of variation (CVs) for intra- and inter-day assays were less than 10.4 and 7.2%, respectively, and the accuracy was &lt;2.4% for both assays. A total of 12 patients who received 2 mg perampanel had C0 values ranging from 70.5 to 451 ng/mL, and the CV showed a large variation of 51.4%. No correlations were observed between the dose-adjusted C0 and the CYP3A4*1G polymorphism. This method was superior to previously reported methods in terms of plasma volume and LOQ and was clinically applicable. Perampanel showed high variations in individual plasma concentrations; however, individual differences could not be predicted from analysis of the CYP3A4*1G polymorphism before perampanel administration. Therefore, after beginning perampanel treatment, the dose should be determined based on the observed plasma concentration. -
Abumiya M.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 2 ) 382 - 387 2020年
研究論文（学術雑誌）
What is known and objective: The purpose of this study was to investigate the relationships among nilotinib plasma trough concentration (C0), low-density lipoprotein (LDL) cholesterol, and PCSK9 plasma concentration in 31 patients with chronic myeloid leukaemia. Methods: Plasma concentrations of nilotinib and PCSK9 were measured by high-performance liquid chromatography and enzyme-linked immunosorbent assays, respectively. Results and discussion: LDL cholesterol concentrations at 1 month after nilotinib treatment were significantly increased compared with those before therapy. The mean C0 (±SD) of nilotinib at 1, 2, and 3 months after nilotinib treatment were 645 ± 516, 902 ± 623, and 951 ± 1088 ng/mL, respectively. Mean PCSK9 concentrations at 3 months after nilotinib treatment were significantly higher than those at the start of therapy (320 vs 257 ng/mL, respectively, P =.019). When the change rate in the PCSK9 concentration induced by nilotinib was classified with a cut-off value of +40%, the change rate in LDL cholesterol in patients with a change rate in PCSK9 of ≥40% was significantly higher than that in patients with a PCSK9 change rate of <40% (67.1% vs 38.0%, P =.043); however, there were no differences in mean nilotinib C0. What is new and conclusion: Nilotinib may lead to hypercholesterolaemia by increasing plasma concentrations of PCSK9 after indirect inhibition of mammalian target of rapamycin (mTOR) complex 1. In addition, certain patients seem to have high sensitivity for nilotinib in a signalling cascade of the PI3K/Akt/mTOR pathway, despite low plasma concentrations of nilotinib. Consequently, nilotinib-induced hypercholesterolaemia could not be predicted based on the plasma concentration of nilotinib.
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Yagishita H.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 44 ( 6 ) 977 - 980 2019年12月
研究論文（学術雑誌）
What is known and objective: Lenvatinib inhibits CYP2C8. (S)-Warfarin is metabolized to (S)-7-hydroxywarfarin by CYP2C9 and (S)-4'-hydroxywarfarin by CYP2C8. Here, we report drug interactions between warfarin and lenvatinib in a patient with CYP2C9*1/*3. Case summary: The patient was administered warfarin. His international normalized ratio (INR) was 1.92 before lenvatinib administration. On day 8 after beginning 12 mg/day lenvatinib, plasma trough concentrations of lenvatinib and (S)-warfarin were 33.3 ng/mL and 0.67 μg/mL, respectively. On day 10, his INR increased to 3.48. What is new and conclusion: Lenvatinib-dependent (S)-warfarin inhibition could involve CYP2C9 and CYP2C8. After initiating warfarin plus lenvatinib, INR assays are necessary.
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熊谷 優, 赤嶺 由美子, 安倍 明, 和田 優貴, 戸沢 智樹, 笹嶋 素子, 熊谷 聡, 橋本 学, 三浦 昌朋
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 55 ( 7 ) 805 - 812 2019年07月
研究論文（学術雑誌）
シスプラチンの腎毒性発現リスクはカルシウム拮抗薬(calcium channel blocker:以下、CCB)との併用によって増強されることが動物にて報告されているが、ヒトでの報告は少ない。今回、シスプラチン投与食道がん患者の腎機能に及ぼす降圧剤の影響を調査した。食道がん放射線化学療法施行患者のうち、降圧剤併用群42名、非併用群71名を調査対象とした。CCB併用群およびアンジオテンシンII受容体拮抗薬(angiotensin II receptor blocker:以下、ARB)あるいはアンジオテンシン変換酵素阻害薬(angiotensin-converting-enzyme inhibitor:以下、ACEI)併用群は非併用群と比べて急性腎障害(acute kidney injury:以下、AKI)の発現頻度が有意に高く(それぞれp=0.001、p=0.011)、またAKI発現時期はシスプラチン治療開始後7日目で最も高かった。シスプラチンと降圧剤の併用によって、AKI発現リスクが高まる可能性が示唆された。シスプラチン治療開始前にCCB、ARBおよびACEI以外の薬剤への変更を提案することが望まれるが、降圧剤使用継続の際は早期からの血液検査のモニタリングが必要と考える。(著者抄録)
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Kobayashi T.
Medical Oncology ( Medical Oncology ) 36 ( 6 ) 2019年06月
研究論文（学術雑誌）
Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration–time curve (AUC0–24) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography–tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC0–24 for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC0–24 in 1236C>T and 2677G>A/T polymorphisms. AUC0–24 was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21) (median 6324.6 ng h/mL vs. 2857.4 ng h/mL, p = 0.028). The AUC0–24 value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC0–24 cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.
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Drug-drug interactions of P-gp substrates unrelated to CYP metabolism
Akamine Y.
Current Drug Metabolism ( Current Drug Metabolism ) 20 ( 2 ) 124 - 129 2019年
研究論文（学術雑誌）
Background:
Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by ≧1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-gp are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs.
Objective:
Since there are no detailed manuscripts that summarizes P-gp interactions unrelated to CYP metabolism, this article reviews the effects of potent P-gp inhibitors and P-gp inducers on the pharmacokinetics of P-gp substrate drugs, including digoxin, talinolol, dabigatran etexilate, and fexofenadine in human studies. In addition, the present outcome were to determine the PK changes caused by DDIs among P-gp substrate drugs without CYP metabolism in human DDI studies.
Conclusion:
Our manuscript concludes that the PK changes of the DDIs among P-gp drugs unrelated to CYP metabolism are less likely to be serious, and it appears to be convincing that the absences of clinical effects caused to the PK changes by the P-gp inducers is predominant compared with the excessive effects caused to those by the P-gp inhibitors. -
Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 43 ( 5 ) 675 - 681 2018年10月
研究論文（学術雑誌）
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未熟児動脈管開存症へのインドメタシン投与が血糖値に与える影響とリスク因子に関する調査
大久保 翔, 赤嶺 由美子, 安達 裕行, 高橋 勉, 三浦 昌朋
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 54 ( 6 ) 705 - 708 2018年06月
研究論文（学術雑誌）
本研究はインドメタシン投与後の未熟児の血糖変動と血糖低下への臨床的介入について調査し、さらに血糖値変化に影響を及ぼす要因について検討した。インドメタシン初回投与の未熟児22名を対象とし、投与前後の血糖値、糖質補充の有無について後方視的に調査した。血糖変化率に影響を及ぼす因子として日齢、在胎週数、出生体重、初回投与量との関連を検討した。インドメタシン投与時に糖質補充を追加していない14例中4例に血糖低下、4例に血糖上昇(それぞれ、変化率の中央値:-31.1%および26.4%)が観察された。4例にインドメタシンによる低血糖予防として追加の糖質補充が行われており、そのなかに血糖低下を来す患児はいなかった。血糖変化率と相関のある因子は観察されなかった。血糖低下の予防として糖質補充の有用性が示されたが、血糖変化は低下のみならず上昇する患者もいることから、投与前後は細めな血糖値の測定が求められる。(著者抄録)
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Comparison electrochemiluminescence immunoassay and latex agglutination turbidimetric immunoassay for evaluation of everolimus blood concentrations in renal transplant patients.
Akamine Y, Sato S, Kagaya H, Ohkubo T, Satoh S, Miura M.
Journal of Clinical Pharmacy and Therapeutics 2018年04月 [査読有り]
研究論文（学術雑誌） 国内共著
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An update on the clinical pharmacokinetics of fexofenadine enantiomers
Akamine Y.
Expert Opinion on Drug Metabolism and Toxicology ( Expert Opinion on Drug Metabolism and Toxicology ) 14 ( 4 ) 429 - 434 2018年04月
研究論文（学術雑誌）
Introduction: Fexofenadine is administered as a racemic mixture of (R)- and (S)-enantiomers. The plasma concentrations of (R)-fexofenadine in humans are about 1.5-fold higher than those of the (S)-enantiomer. Such differences in the pharmacokinetics between fexofenadine enantiomers are likely to be dependent on stereoselectivity for affinity to drug-transporters. Areas covered: This review focuses on elucidation of differences in clinical pharmacokinetics between fexofenadine enantiomers. Expert opinion: Differences in pharmacokinetics between fexofenadine enantiomers were caused by organic anion transporting polypeptide (OATP) 2B1, with a minor contribution from P-glycoprotein (P-gp). In vitro studies using OATP2B1 cRNA showed that (R)-fexofenadine uptake into oocytes is greater than (S)-enantiomer uptake. P-gp inducers, carbamazepine, and inhibitors such as itraconazole and verapamil show greater effects on the pharmacokinetics of (S)-fexofenadine. Apple juice and grape fruit juice, OATP2B1 inhibitors, significantly decrease the exposure of both fexofenadine enantiomers, particularly the (S)-enantiomer, but do not change the t1/2. Rifampicin significantly increases plasma concentrations of both enantiomers through inhibition of OATP1B3, whereas enantioselectivity of fexofenadine uptake by OATP1B3-expressing cells has not been observed. Combinations of multiple transporters such as OATP2B1 and P-gp facilitate enantioselective disposition of fexofenadine. Drug-transporters appear to be capable of chiral discrimination for transport of drugs with an asymmetric center.
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 43 ( 2 ) 181 - 188 2018年04月
研究論文（学術雑誌）
What is known and objective: The anti-tacrolimus antibodies used in commercial immunoassay methods have cross-reactivity with tacrolimus metabolites. The aim of this study was to investigate differences in the effects of CYP3A5 polymorphism on tacrolimus concentrations obtained by four immunoassay methods in renal transplant patients. Methods: Samples (n = 508) were evaluated using four immunoassays (chemiluminescence enzyme immunoassay [CLIA], affinity column-mediated immunoassay [ACMIA], electrochemiluminescence immunoassay [ECLIA] and latex agglutination turbidimetric immunoassay [LTIA]). Results: Bland-Altman plots showed average biases of −0.12 (±1.96 SD: −1.30-1.05) ng/mL for CLIA, −0.30 (−1.59-1.00) ng/mL for ECLIA, 0.42 (−1.21-2.05) ng/mL for ACMIA and 1.88 (−0.51-4.28) ng/mL for LTIA, when considering the mean of the three immunoassays (CLIA, ECLIA and ACMIA). In multiple regression analysis, the difference (CLIA—mean) was affected by haematocrit levels. Differences in ECLIA were correlated with red blood cell counts. For LTIA, CYP3A5 genotype and haematocrit levels were identified as independent predictors for this bias. What is new and conclusion: The results obtained by CLIA, ECLIA and ACMIA were not affected by CYP3A5 polymorphism. However, in LTIA, CYP3A5*1/*3-derived data exhibited an inverse relationship in Bland-Altman analysis (slope: −0.0824). Higher cross-reactivity with 12-hydroxy tacrolimus at lower concentrations may occur in patients with the CYP3A5*1/*3 genotype. Because patients with the CYP3A5*1 allele identified using LTIA may show higher blood concentrations of tacrolimus at lower target concentrations, for example 3.0 ng/mL, compared with other immunoassay methods, there is a need for sufficient consideration of the interpretation of values measured by LTIA.
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Kagaya H.
International Journal of Molecular Sciences ( International Journal of Molecular Sciences ) 19 ( 3 ) 882 - 882 2018年03月
研究論文（学術雑誌）
While tacrolimus and everolimus have common metabolic pathways through CYP3A4/5, tacrolimus is metabolized solely by CYP3A4 in recipients with the CYP3A5*3/*3. The purpose of this study was to evaluate how the area under the blood concentration-time curves (AUC) of tacrolimus could be predicted based on CYP3A5 genotype and the AUC of everolimus in renal transplant patients taking both drugs. The dose-adjusted AUC (AUC/D) of tacrolimus and everolimus were calculated at one month and one year after transplantation. Significant correlations between the AUC/D of tacrolimus and everolimus were found for patients with the CYP3A5*1 allele or CYP3A5*3/*3 at both one month and one year. At both stages, the determination coefficients were higher and the slopes of regression equations were larger for patients with CYP3A5*3/*3 compared to the CYP3A5*1 allele. A good correlation between single doses of tacrolimus and everolimus was found for CYP3A5*3/*3 patients at 1 year after transplantation (r = 0.794, p < 0.001). The variability of the AUC0–24/D of tacrolimus for each CYP3A5 genotype could be predicted based on the AUC0–12/D of everolimus. Clinicians may be able to comprehensively carry out the dose adjustments of tacrolimus and everolimus based on relationship with AUCs of both drugs in each CYP3A5 genotype.
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Akamine Y.
Annals of Clinical Biochemistry ( Annals of Clinical Biochemistry ) 54 ( 6 ) 677 - 685 2017年11月
研究論文（学術雑誌）
Background
This study developed a novel high-performance liquid chromatography (HPLC) method for the simultaneous quantification of clozapine and its active metabolite, N-desmethylclozapine, in human plasma and investigated the effects of various factors, including genetic polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A5, ABCB1 and ABCG2, on the steady-state plasma trough concentrations (C<sub>0</sub>) of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia.
Methods
Forty-five patients had been receiving fixed doses of clozapine for at least four weeks. The CYP2D6 ( CYP2D6*2, CYP2D6*5, CYP2D6*10), CYP3A5 ( CYP3A5*3), ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (421 C > A) genotypes were identified by polymerase chain reaction.
Results
The within- and between-day coefficients of variation (CV) were less than 11.0%, and accuracy was within 9.0% over the linear range from 10 to 2500 ng/mL for both analytes, and their LOQs were each 10 ng/mL. The median C<sub>0</sub>/dose (C<sub>0</sub>/D) ratios of clozapine were significantly higher in patients with the ABCG2 421 A allele than in those with the 421 C/C genotype ( P = 0.010). However, there were no significant differences in C<sub>0</sub>/D ratios of clozapine and N-desmethylclozapine among ABCB1, CYP2D6 or CYP3A5 genotypes. In multiple regression analysis, including polymorphisms, age, body weight and biochemical data of patients, the ABCG2 polymorphism alone was correlated with the C<sub>0</sub>/D ratios of clozapine ( R<sup>2 </sup>= 0.139, P = 0.016).
Conclusions
Among the various CYPs and drug transporters, BCRP appeared to most strongly influence clozapine exposure. Knowledge of the patient’s ABCG2 421 C > A genotype before initiating therapy may be useful when making dosing decisions aimed at achieving optimal clozapine exposure. -
Effects of selective serotonin reuptake inhibitors on the pharmacokinetics of proton pump inhibitors
Tsukasa Uno, Yumiko Akamine, Norio Yasui-Furukori, Takayuki Hirano
Neuropsychiatry (London) 7 ( 4 ) 393 - 397 2017年
研究論文（学術雑誌）
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Influence of everolimus on the pharmacokinetics of tacrolimus in Japanese renal transplant patients
Niioka T.
International Journal of Urology ( International Journal of Urology ) 23 ( 6 ) 484 - 490 2016年06月
研究論文（学術雑誌）
Objectives: To examine whether a trough concentration of everolimus in the therapeutic range of 3-5 ng/mL affects the pharmacokinetics of tacrolimus in renal transplant patients. Methods: A total of 52 Japanese renal transplant patients receiving tacrolimus were enrolled in this study. In 28 of them, everolimus was co-administered on day 14 after surgery. Changes in the dose-adjusted blood trough concentration of tacrolimus from day 14 to 28 after surgery were investigated. Results: The dose-adjusted blood trough concentration of tacrolimus on day 28 was affected by CYP3A5*3/*3 and hemoglobin level (P < 0.001 and P = 0.007), but not by everolimus (P = 0.171). In addition, there was no change in the dose-adjusted blood trough concentration of tacrolimus in patients before or after everolimus coadministration (P = 0.165). On day 28, there was no correlation between the rate of change in the dose-adjusted blood trough concentration of tacrolimus and the blood trough concentration or area under the plasma concentration-time curve from 0 to 12 h for everolimus after initiation of combination therapy (r = 0.341, P = 0.076 and r = 0.234, P = 0.231). Conclusions: A pharmacokinetic interaction between tacrolimus and everolimus was not observed clinically in renal transplant patients. Safe and reliable immunosuppressive therapy in renal transplant patients might be achieved using a combination of tacrolimus and everolimus.
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Akamine Y.
Drug Metabolism and Pharmacokinetics ( Drug Metabolism and Pharmacokinetics ) 30 ( 5 ) 352 - 357 2015年10月
研究論文（学術雑誌）
The stereoselective pharmacokinetics of fexofenadine are associated with OATP2B1-mediated transport, and grapefruit juice (GFJ) is an inhibitor of OATP2B1. Therefore, in this study, we aimed to investigate whether and to what extent GFJ ingestion affected the pharmacokinetics of fexofenadine enantiomers in healthy subjects. In a randomized, two-phase, open-label, crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or GFJ. Ingestion of GFJ significantly decreased the areas under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 39% and 52%, respectively. Subsequently, GFJ increased the mean R/S ratio of the AUC0-24 from 1.58 to 1.96 (P < 0.05). Although GFJ greatly reduced the amounts of (R)- and (S)-fexofenadine excreted into the urine (Ae0-24) by 52% and 61%, respectively, the mean R/S ratios of Ae0-24 and the renal clearances of both enantiomers were unchanged between the control and GFJ phases. GFJ, an OATP2B1 inhibitor, significantly reduced the plasma concentrations of fexofenadine enantiomers, exhibiting clinically moderate effects. The present results suggested that changes in OATP2B1 activity by GFJ may alter the stereoselective pharmacokinetics of fexofenadine and that reduced intestinal OATP2B1 activity may affect the stereoselectivity of fexofenadine.
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Multiple inductive effects of carbamazepine on combined therapy with paliperidone and amlodipine
Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 40 ( 4 ) 480 - 482 2015年08月
研究論文（学術雑誌）
Summary What is known and objective Carbamazepine is a potent inducer of cytochrome P450 3A and P-glycoprotein. However, there are no reports of the effects of carbamazepine on more than one co-administered drug. Case summary A 53-year-old female patient with schizophrenia and hypertension was on paliperidone 12 mg/day and amlodipine 5 mg/day. When carbamazepine was added to this prescription, the plasma concentrations of both drugs decreased dramatically in a dose-dependent manner. Although the patient's psychotic symptoms did not change, as a result, her mean blood pressure increased to 160·1/103·6 mmHg from 138·4/91·4 mmHg at a carbamazepine dose of 600 mg/day. What is new and conclusion Theses cases show the effect of carbamazepine induction on two drugs simultaneously. Care is required when carbamazepine is added to drug regimens including paliperidone or amlodipine alone or together. Carbamazepine is a potent inducer of CYP3A and P-glycoprotein. This cases show the effect of carbamazepine induction on two drugs simultaneously. Care is required when carbamazepine is added to drug regimens including paliperidone or amlodipine alone or together.
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Determinants of the Stereoselective Pharmacokinetics of Fexofenadine
Yumiko Akamine
YAKUGAKU ZASSHI ( Pharmaceutical Society of Japan ) 135 ( 3 ) 473 - 481 2015年03月
研究論文（学術雑誌）
Drug transporters play an important role in the clinical pharmacokinetics of many therapeutic agents. Although it is estimated that about half of all therapeutic agents are chiral, there has been little information on the stereoselective pharmacokinetics related to drug transporters. This review focuses on the drug transporters contributing to the stereoselective pharmacokinetics of fexofenadine enantiomers in humans. Fexofenadine is administered clinically as a racemic mixture, and the plasma concentration of (<i>R</i>)-fexofenadine is about 1.5-fold higher than that of the (<i>S</i>)-enantiomer. Because fexofenadine is poorly metabolized by cytochrome P450s, its pharmacokinetics depends on its drug-transporter activities. First, we examined whether drug-transporter polymorphisms influence fexofenadine enantiomer pharmacokinetics. The findings suggested that a combination of multiple transporters involving organic anion transporting polypeptide (OATP) 2B1, P-glycoprotein (P-gp), and multidrug resistance-associated protein 2 (MRP2) react to stereoselective fexofenadine exposure. Subsequently, we evaluated the roles of P-gp and OATPs in fexofenadine enantiomer pharmacokinetics using these inducer/inhibitors. Coadministration of P-gp inducer/inhibitors significantly altered the pharmacokinetics of fexofenadine enantiomers. In addition, the OATP inhibitors rifampicin and apple juice also affected fexofenadine enantiomer pharmacokinetics. Moreover, in <i>in vitro</i> studies, the uptake of both fexofenadine enantiomers into OATP2B1 cRNA-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (<i>R</i>)-fexofenadine. Taken together, these studies indicated that multiple transporters including P-gp, OATPs, and MRP2 play important roles in fexofenadine enantiomer pharmacokinetics. Furthermore, OATP2B1 is a key determinant of the stereoselective pharmacokinetics of fexofenadine, and drug transporters may have chiral discrimination ability.<br>
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 40 ( 1 ) 98 - 103 2015年02月
研究論文（学術雑誌）
What is known and objective Rifampicin is a potent inducer of P-glycoprotein (P-gp) and inhibitor of organic anion-transporting polypeptides (OATPs), with fexofenadine acting as a substrate for both mechanisms. Simultaneous administration of single- or multiple-dose rifampicin 600 mg significantly increases the concentrations of fexofenadine enantiomers by inhibiting OATP transporters. However, the effects of rifampicin 450 mg are unknown. Here, we evaluated the effects of multiple doses of rifampicin 450 mg on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese volunteers. Methods In this randomized, two-phase, double-blind crossover study, 10 healthy volunteers received rifampicin 450 mg/day or placebo for 7 days. On day 7, fexofenadine 60 mg was co-administered simultaneously. Results and discussion Rifampicin significantly increased the mean area under the plasma concentration-time curve (AUC) of (R)- and (S)-fexofenadine (3·10-fold and 3·48-fold, respectively) and decreased the renal clearance of (R)- and (S)-fexofenadine (0·40-fold and 0·47-fold, respectively), causing marked differences in the mean amounts of these enantiomers excreted into the urine in the rifampicin phase (P < 0·001). These results indicated that multiple doses of rifampicin 450 mg may be sufficient to inhibit the renal influx transporter and OATP-mediated hepatic uptake of both enantiomers. Moreover, these effects may be greater than the P-gp-inductive effects of rifampicin. Therefore, the interactive mechanism of multidose rifampicin may occur through a combination of OATP and P-gp transporters, thereby altering the pharmacokinetics of fexofenadine enantiomers. What is new and conclusions In this study of rifampicin 450 mg, the interactive magnitude of the mean AUC values of fexofenadine enantiomers was higher than that observed in the previous study of rifampicin 600 mg, and no dose-dependent inhibitory effects of rifampicin were observed. These effects may be clinically significant in patients receiving fexofenadine and rifampicin. The AUC of (R)- and (S)-fexofenadine by 450 mg of rifampicin, is a potent inducer of P-glycoprotein and inhibitor of OATPs, rather than 600 mg increased. Interactive mechanism of rifampicin multiple doses seems to occur through a combination of OATP and P-glycoprotein.
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Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers
Akamine Y.
European Journal of Clinical Pharmacology ( European Journal of Clinical Pharmacology ) 70 ( 9 ) 1087 - 1095 2014年09月
研究論文（学術雑誌）
Purpose: We examined the effect of a single apple juice intake on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese subjects. Methods: In a randomized two phase, open-label crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or apple juice. For the uptake studies, oocytes expressing organic anion-transporting polypeptide 2B1 (OATP2B1) were incubated with 100 μM (R)- and (S)-fexofenadine in the presence or absence of 10 % apple juice. Results: One-time ingestion of apple juice significantly decreased the area under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 49 and 59 %, respectively, and prolonged the time to reach the maximum plasma concentration (t max) of both enantiomers (P∈<∈0.001). Although apple juice greatly reduced the amount of (R)- and (S)-fexofenadine excretion into urine (Ae0-24) by 54 and 58 %, respectively, the renal clearances of both enantiomers were unchanged between the control and apple juice phases. For in vitro uptake studies, the uptake of both fexofenadine enantiomers into OATP2B1 complementary RNA (cRNA)-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (R)-fexofenadine. In addition, apple juice significantly decreased the uptake of both enantiomers into OATP2B1 cRNA-injected oocytes. Conclusions: These results suggest that OATP2B1 plays an important role in the stereoselective pharmacokinetics of fexofenadine and that one-time apple juice ingestion probably inhibits intestinal OATP2B1-mediated transport of both enantiomers. In addition, this study demonstrates that the OATP2B1 inhibition effect does not require repeated ingestion or a large volume of apple juice. © 2014 Springer-Verlag.
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The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers
Satoshi Yamada, Hideo Shiohira, Norio Yasui-Furukori, Tomonori Tateishi, Yumiko Akamine, Tsukasa Uno
European Journal of Clinical Pharmacology ( Springer Science and Business Media LLC ) 69 ( 7 ) 1423 - 1428 2013年07月
研究論文（学術雑誌）
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Kusuhara H.
Drug Metabolism and Disposition ( Drug Metabolism and Disposition ) 41 ( 1 ) 206 - 213 2013年01月
研究論文（学術雑誌）
The effect of rifampicin on the pharmacokinetics of fexofenadine enantiomers was examined in healthy subjects who received fexofenadine alone or with single or multiple doses of rifampicin (600 mg). A single coadministered dose of rifampicin significantly decreased the oral clearance (CL tot/F) and renal clearance (CLr) of S- and R-fexofenadine by 76 and 62%, and 73 and 62%, respectively. Even after multiple doses, rifampicin significantly decreased these parameters, although the effect on the CLtot/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CLtot/F of fexofenadine enantiomers, whereas the stereoselectivity in the CLr persisted. Rifampicin inhibited the uptake of fexofenadine enantiomers by human hepatocytes via organic anion transporter (OAT) OATP1B3 and its basal-to-apical transport in Caco-2 cells, but not OAT3-mediated or multidrug and toxic compound extrusion 1 (MATE1) - mediated transport. The plasma-unbound fraction of S-fexofenadine was 1.8 times higher than that of R-fexofenadine. The rifampicin-sensitive uptake by hepatocytes was 1.6 times higher for R-fexofenadine, whereas the transport activities by OATP1B3, OAT3, MATE1, or P-glycoprotein were identical for both enantiomers. S-fexofenadine is a more potent human histamine H1 receptor antagonist than R-fexofenadine. In conclusion, rifampicin has multiple interaction sites with fexofenadine, all of which contribute to increasing the area under the curve of fexofenadine when they are given simultaneously, to surpass the effect of the induction of P-glycoprotein elicited by multiple doses. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
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Psychotropic Drug–Drug Interactions Involving P-Glycoprotein
Yumiko Akamine, Norio Yasui-Furukori, Ichiro Ieiri, Tsukasa Uno
CNS Drugs ( Springer Science and Business Media LLC ) 26 ( 11 ) 959 - 973 2012年11月
研究論文（学術雑誌）
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Hideo Shiohira, Norio Yasui-Furukori, Satoshi Yamada, Tomonori Tateishi, Yumiko Akamine, Tsukasa Uno
Pharmaceutical Research ( Springer Science and Business Media LLC ) 29 ( 8 ) 2310 - 2316 2012年08月
研究論文（学術雑誌）
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Junji Saruwatari, Norio Yasui-Furukori, Takenori Niioka, Yumiko Akamine, Ayaka Takashima, Sunao Kaneko, Tsukasa Uno
Journal of Clinical Psychopharmacology ( Ovid Technologies (Wolters Kluwer Health) ) 32 ( 2 ) 195 - 199 2012年04月
研究論文（学術雑誌）
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Carbamazepine differentially affects the pharmacokinetics of fexofenadine enantiomers
Akamine Y.
British Journal of Clinical Pharmacology ( British Journal of Clinical Pharmacology ) 73 ( 3 ) 478 - 481 2012年03月
研究論文（学術雑誌）
Aim: This aim of this study was to characterize the impact of the P-glycoprotein (P-gp) inducer, carbamazepine, on fexofenadine enantiomer pharmacokinetics. Methods: Twelve healthy volunteers initially received a 60mg dose of fexofenadine alone. Subsequently, a 100mg dose of carbamazepine was administered three times daily (300mg day -1), and on day 7, fexofenadine was co-administered. Results: Carbamazepine significantly decreased the area under the plasma concentration-time curve and the amount excreted into the urine of (S)- and (R)-fexofenadine. The P-gp inducer showed a greater effect on the pharmacokinetic parameters of (S)-fexofenadine. Conclusion: This study indicates that carbamazepine may alter the pharmacokinetics of fexofenadine enantiomers. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.
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The Role of Drug Transporters on Psychotropic Penetration of the Blood–Brain Barrier
Akamine Yumiko, China Kayoko, Uno Tsukasa
Clinical Neuropsychopharmacology and Therapeutics ( 日本臨床精神神経薬理学会 ) 3 8 - 14 2012年 [査読有り]
研究論文（学術雑誌）
At the Blood–Brain barrier (BBB), the superfamily of ATP-binding cassette (ABC) transporters includes the ABCB1 subfamily corresponding to P-glycoprotein (P-gp), the ABCC subfamilies of multidrug resistance-associated proteins (MRPs), and the ABCG2 subfamily corresponding to breast cancer resistance protein (BCRP). These efflux transporters are located mainly in the endothelial cells forming the BBB and prevent the entry of xenobiotics into the brain. Since psychotropics act on target sites of the central nervous system (CNS) in the brain, it is very important to know these transporters' roles at the BBB and to determine the brain drug concentrations at the targeted sites of the CNS. However, there is little information on human brain concentrations of psychotropics. Recent studies have demonstrated that brain concentrations of many psychotropics are significantly higher in P-gp-knockout mice than in wild-type mice. This result implies that P-gp may be a key player in the regulation of brain psychotropic pharmacokinetics and possibly causes the P-gp-mediated drug interaction at the BBB. In this review, we discuss the current findings concerning the role of drug transporters on the concentrations of psychotropics in the brain and summarize the available in vivo studies related to psychotropics.
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遺伝子情報を臨床で有効に生かすには テーラーメイド治療に向けて
赤嶺 由美子, 宇野 司
九州薬学会会報 ( 九州山口薬学会 ) ( 65 ) 7 - 12 2011年10月
研究論文（学術雑誌）
薬剤師にとってゲノム薬理学情報が医薬品適正使用推進のための重要なツールとなることは明らかである。薬物代謝酵素ならびに薬物トランスポーターの遺伝子多型とその臨床的意義について概説すると共に、薬剤師にとって臨床上重要な遺伝子変異(バイオマーカー)について述べた。代表的な薬物代謝酵素としてCYP2C19、CYP2D6、CYP2C9、CYP3A5、薬物トランスポーターとしてP-gp、OATPs、注目すべき遺伝子変異としてKRAS遺伝子、EGFR遺伝子を挙げた。
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Yumiko Akamine, Norio Yasui-Furukori, Midori Kojima, Yoshimasa Inoue, Tsukasa Uno
Journal of Separation Science ( Wiley ) 33 ( 21 ) 3292 - 3298 2010年11月
研究論文（学術雑誌）
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Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers
Akamine Y.
Xenobiotica ( Xenobiotica ) 40 ( 11 ) 782 - 789 2010年11月
研究論文（学術雑誌）
This study investigated an association of SLCO (encoding organic anion-transporting polypeptides (OATP), 1B1, 1B3, and 2B1), ABCB1 (P-glycoprotein (P-gp)), ABCC2 multidrug resistance protein 2 (MRP2), and ABCG2 (breast cancer resistance protein (BCRP)) polymorphisms with fexofenadine enantiomer pharmacokinetics after an oral dose of fexofenadine (60mg) in 24 healthy subjects. The area under the plasma concentration-time curve (AUC 0-24) of S-fexofenadine, but not R-fexofenadine, was significantly lower in subjects with a SLCO2B1*1/*1 allele as compared to subjects with a *3 allele (p0.031). The AUC024 of S-fexofenadine was significantly lower in subjects with a wild-type combination of SLCO2B1*1/*1/ ABCB1 1236CC, SLCO2B1*1/*1/ABCB1 3435CC, SLCO2B1*1/*1/ ABCC2-24CC, and ABCB1 1236CC/3435CC/ABCC2-24CC compared to other polymorphic genotypes (p0.010, 0.033, 0.022, and 0.036, respectively), whereas there was no difference in the AUC024 between the SLCO1B1/1B3 plus ABCB1 and ABCC2 groups. The pharmacokinetic properties of S-fexofenadine are affected by a single polymorphism of SLCO2B1 in combination with several polymorphisms of ABCB1 C1236T, C3435T, and ABCC2 C-24T. However, the ABCG2 polymorphism was not associated with fexofenadine pharmacokinetics. These findings suggest that a combination of multiple transporters, including OATP, P-gp, and MRP2, reacts strongly to fexofenadine exposure in the small intestine and liver, resulting in different dispositions of both enantiomers. © 2010 Informa UK, Ltd.
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P糖たんぱく質を介した薬物相互作用の臨床研究 Fexofenadine各光学異性体の体内動態
赤嶺 由美子, 宇野 司
医薬品相互作用研究 ( (一社)医薬品相互作用研究会 ) 33 ( 2 ) 45 - 50 2010年01月
研究論文（学術雑誌）
フェキソフェナジンはヒスタミンH1受容体拮抗薬であり、アレルギー性疾患の治療薬として広く使用されている。フェキソフェナジンはR体とS体の光学異性体を持つラセミ化合物で、両方の光学異性体は臨床的に等しい薬理作用をもつが、体内動態は異なる挙動を示す。光学異性体間における薬物動態の違いについて概説した。また、P糖蛋白質阻害剤であるイトラコナゾールとベラパミル、P糖蛋白質誘導剤であるカルバマゼピンと、フェキソフェナジン光学異性体との薬物相互作用について述べた。
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Effects of the P-glycoprotein Inducer Carbamazepine on Fexofenadine Pharmacokinetics
Satoshi Yamada, Norio Yasui-Furukori, Yumiko Akamine, Sunao Kaneko, Tsukasa Uno
Therapeutic Drug Monitoring ( Ovid Technologies (Wolters Kluwer Health) ) 31 ( 6 ) 764 - 768 2009年12月
研究論文（学術雑誌）