研究等業績 - 原著論文 - 菊地　正史

Bile Acid–Drug Interaction via Organic Anion-Transporting Polypeptide 4C1 Is a Potential Mechanism of Altered Pharmacokinetics of Renally Excreted Drugs

Minami Yamauchi, Toshihiro Sato, Ayana Otake, Masaki Kumondai, Yu Sato, Masafumi Kikuchi, Masamitsu Maekawa, Hiroaki Yamaguchi, Takaaki Abe, Nariyasu Mano

International Journal of Molecular Sciences ( MDPI AG )  23 ( 15 ) 8508 - 8508   2022年07月  [査読有り]

研究論文（学術雑誌）  

Patients with liver diseases not only experience the adverse effects of liver-metabolized drugs, but also the unexpected adverse effects of renally excreted drugs. Bile acids alter the expression of renal drug transporters, however, the direct effects of bile acids on drug transport remain unknown. Renal drug transporter organic anion-transporting polypeptide 4C1 (OATP4C1) was reported to be inhibited by chenodeoxycholic acid. Therefore, we predicted that the inhibition of OATP4C1-mediated transport by bile acids might be a potential mechanism for the altered pharmacokinetics of renally excreted drugs. We screened 45 types of bile acids and calculated the IC50, Ki values, and bile acid–drug interaction (BDI) indices of bile acids whose inhibitory effect on OATP4C1 was >50%. From the screening results, lithocholic acid (LCA), glycine-conjugated lithocholic acid (GLCA), and taurine-conjugated lithocholic acid (TLCA) were newly identified as inhibitors of OATP4C1. Since the BDI index of LCA was 0.278, LCA is likely to inhibit OATP4C1-mediated transport in clinical settings. Our findings suggest that dose adjustment of renally excreted drugs may be required in patients with renal failure as well as in patients with hepatic failure. We believe that our findings provide essential information for drug development and safe drug treatment in clinics.

DOI PubMed

Shifting the linear range of the calibration curves for the quantification of oral molecular-targeted anticancer drugs and the active metabolite in human plasma using LC-ESI-MS/MS

Tensei Hirasawa, Masafumi Kikuchi, Shinya Takasaki, Masaki Kumondai, Yu Sato, Toshihiro Sato, Eishi Imoto, Yoshihiro Hayakawa, Masamitsu Maekawa, Nariyasu Mano

Medical Mass Spectrometry ( (一社)日本医用マススペクトル学会 )  6 ( 1 ) 52 - 63   2022年06月  [査読有り]

研究論文（学術雑誌）  

DOI

Metabolic Alteration Analysis of Steroid Hormones in Niemann-Pick Disease Type C Model Cell Using Liquid Chromatography/Tandem Mass Spectrometry.

Ai Abe, Masamitsu Maekawa, Toshihiro Sato, Yu Sato, Masaki Kumondai, Hayato Takahashi, Masafumi Kikuchi, Katsumi Higaki, Jiro Ogura, Nariyasu Mano

International journal of molecular sciences   23 ( 8 )   2022年04月  [査読有り]

研究論文（学術雑誌）  

Niemann-Pick disease type C (NPC) is an autosomal recessive disease caused by a functional deficiency of cholesterol-transporting proteins in lysosomes, and exhibits various clinical symptoms. Since mitochondrial dysfunction in NPC has recently been reported, cholesterol catabolism to steroid hormones may consequently be impaired. In this study, we developed a comprehensive steroid hormone analysis method using liquid chromatography/tandem mass spectrometry (LC-MS/MS) and applied it to analyze changes in steroid hormone concentrations in NPC model cells. We investigated the analytical conditions for simultaneous LC-MS/MS analysis, which could be readily separated from each other and showed good reproducibility. The NPC phenotype was verified as an NPC model with mitochondrial abnormalities using filipin staining and organelle morphology observations. Steroid hormones in the cell suspension and cell culture medium were also analyzed. Steroid hormone analysis indicated that the levels of six steroid hormones were significantly decreased in the NPC model cell and culture medium compared to those in the wild-type cell and culture medium. These results indicate that some steroid hormones change during NPC pathophysiology and this change is accompanied by mitochondrial abnormalities.

DOI PubMed

宮城県における改訂薬学教育モデル・コアカリキュラムに基づく実務実習の実施状況と薬剤師の意識調査

大内 友季江, 中井 啓, 菊地 正史, 中村 浩規, 森川 昭正, 石澤 文章, 村井 ユリ子

医療薬学 ( (一社)日本医療薬学会 )  47 ( 12 ) 674 - 687   2021年12月  [査読有り]

研究論文（学術雑誌）  

2019年度に、改訂版薬学教育モデル・コアカリキュラム(改訂コアカリ)に基づく薬学実務実習(実習)の実施状況と薬剤師の意識に関するアンケート調査を行い、実習を受け入れた薬局27施設、薬局薬剤師69人、病院14施設、病院薬剤師151人から回答を得た。その結果、薬局では大学との直接的連携、病院では薬局や大学との直接的連携を望んでおり、改訂コアカリで求められる地域住民の薬物治療、在宅医療、セルフメディケーションの実習などは74.1%の薬局で、患者の薬物治療の経時的なモニタリングなどの実習は85.7%の病院でそれぞれ概ね対応できたと回答した。また、責任薬剤師や指導薬剤師以外の薬剤師の実習への関与は少なかった。改訂コアカリに基づく実習は改善の余地があり、施設全体の薬剤師が実習に関与するような体制構築、指導薬剤師の養成および好事例の共有に対応すべきと考えられた。

新型コロナウイルス感染症に対応した病院実務実習プログラムの評価

菊地 正史, 佐藤 裕, 佐藤 紀宏, 前川 正充, 眞野 成康

日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 )  57 ( 11 ) 1256 - 1261   2021年11月  [査読有り]

研究論文（学術雑誌）  

東北大学病院では、2020年度第II期の病院実務実習生25名に対して、Googleのオンラインシステムを活用し、新型コロナウイルス感染症に対応した病院実務実習プログラムを実践した。実習11週目の指導薬剤師による概略評価11項目の平均は2.5〜3.1であり、すべて臨床で実習を実施した2019年度と比べて、8項目において有意差が認められなかった。また、代表的8疾患にかかわった割合は92〜100%であり、2019年度と比べて有意差が認められなかった。さらに、Webアンケートでは、多くの実習項目の理解度と満足度は、2019年度と比べてともに高い傾向が認められた。個人情報を除いた実処方箋や実症例の情報などを用い、指導薬剤師が模擬医師や模擬患者となることで、特に知識を中心とする実習はオンラインで対応可能であることが示唆された。(著者抄録)

KRP-203 is a Desirable Immunomodulator for Islet Allotransplantation.

Ibrahim Fathi, Ryuichi Nishimura, Takehiro Imura, Akiko Inagaki, Norifumi Kanai, Akira Ushiyama, Masafumi Kikuchi, Masamitsu Maekawa, Hiroaki Yamaguchi, Masafumi Goto

Transplantation   106 ( 5 ) 963 - 972   2021年07月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: The current standard immunosuppressive regimens, calcineurin inhibitors, have diabetogeneic and anti-vascularization effects on islet grafts. KRP-203, a sphyngosine-1-phosphate functional antagonist, exerts its immunomodulatory function through lymphocyte sequestration. However, the effect of this antagonist on islets is unclear. We examined the effect of KRP-203 on the islet function and vascularization and sought a calcineurin-free regimen for islet allotransplantation. METHODS: KRP-203 was administered for 14 days to mice, then diabetogenic effect was evaluated by blood glucose levels and a glucose tolerance test. Static glucose stimulation, the breathing index, and insulin/DNA were examined using isolated islets. Islet neovascularization was evaluated using a multi-photon laser scanning microscope (MPLSM). After islet allotransplantation with either KRP-203 alone, Sirolimus alone, or both in combination, the graft survival was evaluated by blood glucose levels and immunohistochemical analyses. A mixed lymphocyte reaction was also performed to investigate the immunological characteristics of KRP-203 and Sirolimus. RESULTS: No significant differences in the blood glucose levels or glucose tolerance were observed between the control and KRP-203 groups. Functional assays after islet isolation were also comparable. The MPLSM showed no inhibitory effect of KRP-203 on islet neovascularization. Although allogeneic rejection was effectively inhibited by KRP-203 monotherapy (44%), combination therapy prevented rejection in most transplanted mice (83%). CONCLUSIONS: KRP-203 is a desirable immunomodulator for islet transplantation due to the preservation of the endocrine function and lack of interference with islet neovascularization. The combination of KRP-203 with low-dose Sirolimus may be promising as a calcineurin-free regimen for islet allotransplantation.

DOI PubMed

Enhancement and evaluation of a prescription audit system for direct oral anticoagulants using a check sheet.

Naoto Ishikawa, Hanae Oshikiri, Shinya Takasaki, Masafumi Kikuchi, Taku Obara, Kazutoshi Akasaka, Masaki Matsuura, Hiroaki Yamaguchi, Nariyasu Mano

Journal of pharmaceutical health care and sciences   7 ( 1 ) 22 - 22   2021年06月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Renal function and use of concomitant medications should be carefully monitored in patients subjected to treatment with direct oral anticoagulants (DOACs); the dose should be individually designed for each patient. Owing to the complex therapeutic indications and dose reduction criteria, pharmacists exercise caution when determining the optimal dose for each patient. A DOAC check sheet has been developed that is automatically printed in the dispensing room at the same time as the prescription and can be used by pharmacists to dispense DOACs promptly and correctly. The purpose of this study was to evaluate the system for dispensing DOACs using a check sheet. METHODS: The study was conducted at Tohoku University Hospital in Japan; prescriptions containing DOACs dispensed by the hospital pharmacists were evaluated. The DOAC check sheet described indications, dosage regimens, dose reduction criteria, and contraindications for each drug and included the patient's information. The check sheet was set to print automatically in the dispensing room at the same time as the prescription when an inpatient was prescribed DOACs. This check sheet was evaluated using a prescription survey and a questionnaire for pharmacists. RESULTS: The usefulness of this check sheet for the correct use of DOACs was evaluated. There were four inquiries out of 642 (0.6%) prescriptions from pharmacists to physicians regarding DOAC prescriptions, such as the dose introduced before DOAC check sheet utilization, and there were 21 out of 905 (2.3%) prescriptions when the DOAC check sheet was used it, showing a significant increase (p = 0.0089). After the introduction of this sheet, overdoses of DOACs were identified at the time of dispensing. Of the 52 pharmacists who responded to the questionnaire, 51 (98%) stated that the check sheet was useful. CONCLUSION: The use of the DOAC check sheet is likely to render safety to DOAC drug therapy for individual patients.

DOI PubMed

Establishment of an analytical method for simultaneous quantitation of CDK4/6 inhibitors, aromatase inhibitors, and an estrogen receptor antagonist in human plasma using LC-ESI-MS/MS.

Yu Sato, Kensuke Shigeta, Tensei Hirasawa, Toshihiro Sato, Jiro Ogura, Masamitsu Maekawa, Akiko Ebata, Yohei Hamanaka, Hiroshi Tada, Takanori Ishida, Masafumi Kikuchi, Nariyasu Mano

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences   1173   122655 - 122655   2021年03月  [査読有り]

研究論文（学術雑誌）  

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, and ribociclib) are used to treat human epithelial growth factor receptor (HER)-2 negative and hormone receptor (HR) positive advanced breast cancer in combination with aromatase inhibitors (letrozole, anastrozole) or an estrogen receptor antagonist (fulvestrant). Administration of these drugs frequently causes severe side effects, such as neutropenia and diarrhea. Therefore, therapeutic drug monitoring (TDM) of CDK4/6 inhibitors, aromatase inhibitors, and the estrogen receptor antagonist is considered important for ensuring the efficacy and safety of these drugs. In this study, we describe a simple, highly sensitive, and specific liquid chromatography/electrospray ionization tandem mass spectrometry method for simultaneous quantitation of the concentrations of palbociclib, abemaciclib, ribociclib, letrozole, anastrozole, and fulvestrant. In addition, we analyzed plasma samples from patients with HER2-negative and HR-positive advanced breast cancer treated with these compounds using this novel method. In our method, the intra-assay relative error (RE) values ranged from -12.8% to 12.9%, the inter-assay RE values ranged from -4.8% to 6.2%, and the coefficient of variation (CV) values for intra- and inter-assay were ≤8.6% and ≤13.3%, respectively. The analytes showed good stability with RE values ranging from -13.5% to 13.6% and CV values <10.4%. Moreover, all the samples from patients were successfully quantified, and were within the range of measurement. This method can be used for TDM of routine anticancer drugs in clinical practice and for pharmacokinetics/pharmacodynamics research in future studies.

DOI PubMed

High-throughput liquid chromatography/electrospray ionization-tandem mass spectrometry method using in-source collision-induced dissociation for simultaneous quantification of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in human plasma.

Tensei Hirasawa, Masafumi Kikuchi, Kensuke Shigeta, Shinya Takasaki, Yu Sato, Toshihiro Sato, Jiro Ogura, Koichi Onodera, Noriko Fukuhara, Yasushi Onishi, Masamitsu Maekawa, Nariyasu Mano

Biomedical chromatography : BMC   35 ( 8 ) e5124   2021年03月  [査読有り]

研究論文（学術雑誌）  

Recent studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKIs) could improve treatment efficacy and safety. A simple analytical method using high-performance LC/electrospray ionization-tandem mass spectrometry has been developed and validated for simultaneous quantification of BCR-ABL and Bruton's TKIs used for chronic leukemia (imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib) in human plasma. Although these structures and physical properties are similar, owing to their different linear ranges, simultaneously determining the plasma levels of these five TKIs by applying optimal MS parameters remains difficult. A quantitative range exceeding 60,000-fold was required, and the linear dynamic ranges of imatinib, bosutinib, and nilotinib were limited because of the presence of a saturated detection signal. In this study, we applied the in-source collision-induced dissociation technique to control the ion amounts in mass spectrometry. This new method allowed rapid determination within 5 min with simple pretreatment. The method was validated according to the US Food and Drug Administration guidelines. Moreover, all samples of patients with chronic leukemia were successfully measured and their values were within the linear range of measurement. Therefore, our high-throughput analytical system is useful to measure the plasma concentrations of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in clinical practice.

DOI PubMed

Development of a simultaneous analytical method for clozapine and its metabolites in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry with linear range adjusted by in-source collision-induced dissociation.

Toshihiro Sato, Masato Suzuka, Yuji Sato, Riko Iwabuchi, Daisuke Kobayashi, Jiro Ogura, Shinya Takasaki, Maki Yokota, Taku Tsukamoto, Yoshihiro Hayakawa, Masafumi Kikuchi, Masamitsu Maekawa, Nariyasu Mano

Biomedical chromatography : BMC   35 ( 7 ) e5094   2021年02月  [査読有り]

研究論文（学術雑誌）  

Clozapine (CLZ) is a key drug in treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of CLZ and its metabolites, N-desmethylclozapine and clozapine N-oxide, is required to monitor and manage the risks of side effects. Although quantification methods for TDM have been developed for CLZ and its metabolites, they were not sufficiently accurate for the quantification of CLZ owing to the upper limits of the calibration curves. An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry was developed and validated for the simultaneous measurement of CLZ and its metabolites in human plasma. To expand the concentration range of the calibration curves, we used a linear range shift technique using in-source collision-induced dissociation (CID). Using our approach, the linearity and quantitative range were improved compared to those reported by previous studies, and were sufficient for TDM in clinical practice. The intra- and inter-assay accuracy was 84.6%-114.8%, and the intra- and inter-assay precisions were ≤9.1% and ≤9.9%, respectively. Moreover, all samples from patients with treatment-resistant schizophrenia were successfully quantified. Therefore, our novel analytical method using in-source CID had the appropriate performance to measure the plasma concentrations of CLZ and its metabolites for TDM in clinical practice.

DOI PubMed

Simultaneous analysis of drugs administered to lung-transplanted patients using liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring.

Shinya Takasaki, Tensei Hirasawa, Yu Sato, Masamitsu Maekawa, Taku Tsukamoto, Masafumi Kikuchi, Jiro Ogura, Yoshihiro Hayakawa, Yasushi Matsuda, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Yoshinori Okada, Hiroaki Yamaguchi, Nariyasu Mano

Biomedical chromatography : BMC   35 ( 6 ) e5067   2021年01月  [査読有り]

研究論文（学術雑誌）  

Several drugs are administered to lung-transplanted patients, which are monitored using therapeutic drug monitoring (TDM). Therefore, we developed and validated a liquid chromatography-tandem mass spectrometry method to simultaneously analyze immunosuppressive drugs such as mycophenolic acid, antifungal drugs such as voriconazole and itraconazole, and its metabolite hydroxyitraconazole. Chromatographic separation was achieved using a C18 column and gradient flow of mobile phase comprising 20 mM aqueous ammonium formate and 20 mM ammonium formate-methanol solution. A simple protein precipitation treatment was performed using acetonitrile/methanol and mycophenolic acid-2 H3 , voriconazole-2 H3 , itraconazole-2 H4 , and hydroxyitraconazole-2 H4 as internal standards. The linearity ranges of mycophenolic acid, voriconazole, itraconazole, and hydroxyitraconazole were 100-20,000, 50-10,000, 5-1000, and 5-1000 ng/mL, respectively. The retention time of each target was less than 2 min. The relative errors in intra- and inter-day were within ±7.6%, the coefficient of variation was 8.9% or less for quality control low, medium, and high, and it was 15.8% or less for lower limit of quantitation. Moreover, the patient samples were successfully quantified, and they were within the linear range of measurements. Therefore, our new method may be useful for TDM in lung-transplanted patients.

DOI PubMed

Clinical importance of blood drug concentration of oral molecular targeted drugs for renal cell carcinoma

Takasaki, S., Kawasaki, Y., Kikuchi, M., Ito, A., Yamaguchi, H., Mano, N.

Journal of Pharmacy and Pharmaceutical Sciences   24   127 - 136   2021年

研究論文（学術雑誌）  

PURPOSE: Therapeutic drug monitoring (TDM) is widely used in clinical practice to maximize drug efficacy and minimize toxicities. Currently, it is also practiced in the use of oral molecular targeted drugs. The objective of this study was to assess the clinical importance of measuring the systemic concentration of oral molecular targeted drugs used to treat renal cell carcinoma (RCC). METHODS: The systemic concentrations of the oral molecular targeted drugs sorafenib, sunitinib, axitinib, pazopanib, and everolimus used for RCC were useful for therapeutic interventions, and clinical outcomes were evaluated retrospectively. RESULTS: The interventional use of systemic drug concentration was confirmed in 26 of 87, and their categories are presented. The systemic concentration of sunitinib was useful in dose reduction and/or discontinuation (n = 10), dose escalation (n = 3), and adherence monitoring (n = 2). Nine of the 10 patients whose dose was reduced showed reduced adverse event. Two patients who were intervened in adherence monitor showed improved adherence. For axitinib, dose reduction and/or discontinuation (n = 1) and dose escalation (n = 6) were confirmed. For pazopanib, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, both of them were confirmed to have reduced adverse events. For everolimus, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, a patient with reduced dose recovered from adverse events. Interventions for sorafenib were not identified. CONCLUSIONS: This study demonstrated that systemic concentrations of oral molecular targeted drugs for RCC were considered to be clinically useful for dose adjustment, monitoring of treatment adherence, and the detection of drug interactions. Moreover, this information could be successfully used to guide individualized therapy to maximize the antitumor effects of these drugs.

DOI PubMed

新薬学教育6年制を考える 新型コロナウイルス感染症に対応した病院実務実習プログラムの構築と実践

菊地 正史, 佐藤 裕, 佐藤 紀宏, 前川 正充, 眞野 成康

医薬品相互作用研究 ( (一社)医薬品相互作用研究会 )  44 ( 3 ) 191 - 195   2020年12月

研究論文（学術雑誌）  

Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation.

Hiroshi Yabuki, Yasushi Matsuda, Tatsuaki Watanabe, Shunsuke Eba, Fumihiko Hoshi, Takashi Hirama, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Akira Sakurada, Masafumi Kikuchi, Hiroaki Yamaguchi, Nariyasu Mano, Yoshinori Okada

Clinical transplantation   34 ( 12 ) e14088   2020年12月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: The therapeutic drug monitoring of mycophenolic acid (MPA) has been investigated for renal and heart transplantations; however, its usefulness in lung transplantation is unclear. METHODS: The MPA area under the plasma concentration-time curve (AUC) was calculated in 59 adult lung transplant recipients. The MPA AUC0-12 s were compared among the three groups determined by the presence of adverse events (no events, infection, and chronic lung allograft dysfunction [CLAD]). Next, MPA AUC0-12 thresholds for the adverse events were identified by receiver operating characteristic analysis. Cumulative occurrence rate of the adverse events was compared between two groups (adequate and inadequate groups) according to the thresholds. RESULTS: The MPA AUC0-12 s in the no event, infection, and CLAD groups were 30.3 ± 6.5, 36.8 ± 10.7, and 20.6 ± 9.6 µg·h/mL, respectively (P = .0027), while the tacrolimus trough levels were similarly controlled in the groups. The thresholds of MPA AUC0-12 for the occurrence of infection and CLAD were 40.5 and 22.8 µg·h/mL, respectively. The cumulative occurrence rate of adverse events of adequate group (15.3%) was significantly lower than that of inadequate group (56.0%) (P = .0050). CONCLUSIONS: The MPA AUC0-12 may affect the occurrence of adverse events in lung transplant recipients.

DOI PubMed

Development of a Diagnostic Screening Strategy for Niemann-Pick Diseases Based on Simultaneous Liquid Chromatography-Tandem Mass Spectrometry Analyses of N-Palmitoyl-O-phosphocholine-serine and Sphingosylphosphorylcholine.

Anna Iwahori, Masamitsu Maekawa, Aya Narita, Akie Kato, Toshihiro Sato, Jiro Ogura, Yu Sato, Masafumi Kikuchi, Atsuko Noguchi, Katsumi Higaki, Torayuki Okuyama, Tsutomu Takahashi, Yoshikatsu Eto, Nariyasu Mano

Biological & pharmaceutical bulletin   43 ( 9 ) 1398 - 1406   2020年09月  [査読有り]

研究論文（学術雑誌）  

Early diagnosis of Niemann-Pick diseases (NPDs) is important for better prognosis of such diseases. N-Palmitoyl-O-phosphocholine-serine (PPCS) is a new NPD biomarker possessing high sensitivity, and with its combination with sphingosylphosphocholine (SPC) it may be possible to distinguish NPD-C from NPD-A/B. In this study, a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (method 1) and a validated LC-MS/MS analysis (method 2) of PPCS and SPC were developed, and we have proposed a diagnostic screening strategy for NPDs using a combination of serum PPCS and SPC concentrations. Nexera and API 5000 were used as LC-MS/MS systems. C18 columns with lengths of 10 and 50 mm were used for method 1 and 2, respectively. 2H3-Labeled PPCS and nor-SPC were used as internal standards. Selective reaction monitoring in positive-ion mode was used for MS/MS. Run times of 1.2 and 8 min were set for methods 1 and 2, respectively. In both methods 1 and 2, two analytes showed high linearity in the range of 1-4000 ng/mL. Method 2 provided high accuracy and precision in method validation. Serum concentrations of both analytes were significantly higher in NPD-C patients than those of healthy subjects in both methods. Serum PPCS correlated between methods 1 and 2; however, it was different in the case of SPC. The serum PPCS/SPC ratio was different in healthy subjects, NPD-C, and NPD-A/B. These results suggest that using a combination of the two LC-MS/MS analytical methods for PPCS and SPC is useful for diagnostic screening of NPDs.

DOI PubMed

Development of a precise quantitative method for monitoring sirolimus in whole blood using LC/ESI-MS/MS.

Kensuke Shigeta, Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Hisashi Oishi, Tetsu Sado, Yasushi Matsuda, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi

Biomedical chromatography : BMC   34 ( 8 ) e4853   2020年08月  [査読有り]

研究論文（学術雑誌）  

Sirolimus is used on patients after solid organ transplantation and on lymphangioleiomyomatosis (LAM) patients, and therapeutic drug monitoring is required in clinical practice. We have previously reported an accurate method for quantitative determination of sirolimus, but its sample preparation step was complicated. In this study, we developed a modified liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for sirolimus quantification. A supported liquid extraction cartridge was used to purify sirolimus from whole blood and ion suppression was mostly prevented. The validation results met the acceptance criteria. This method was compared with the antigen conjugated magnetic immunoassay (ACMIA) and our previously reported method, using whole blood samples from LAM patients. Comparison of the Bland-Altman plots of the currently developed method and the previous method revealed no significant difference between the two methods (mean bias, -2.02%; 95% CI, -7.81-3.78). The values obtained using ACMIA were significantly higher than those obtained using the current method by 13.87% (95% CI, 6.49-21.25) owing to cross-reactivity. The degrees of cross reactivities in LAM patients and in organ transplant patients were similar, and our LC/ESI-MS/MS method precisely measured the blood concentrations of sirolimus.

DOI PubMed

Importance of Therapeutic Drug Monitoring to Detect Drug Interaction between Pazopanib and Warfarin: A Case Report.

Shinya Takasaki, Hisanobu Adachi, Yoshihide Kawasaki, Masafumi Kikuchi, Akihiro Ito, Nariyasu Mano

Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques   23   200 - 205   2020年  [査読有り]

研究論文（学術雑誌）  

Pazopanib is an orally available multi-tyrosine kinase inhibitor and has been used to treat renal cell carcinoma (RCC). Here, we report the case of a patient with RCC with an increased prothrombin time- international normalized ratio (PT-INR) due to pazopanib therapy. In addition, we have reported the change in the blood levels of pazopanib. A 75-year-old man underwent a left nephrectomy for RCC. Four years later, his cancer recurred and pazopanib therapy was initiated. He was also taking warfarin for atrial fibrillation and his PT-INR was constant at approximately 2. His warfarin dose was reduced from 3.5 mg/day to 3.0 mg/day on day 10 because his PT-INR increased from 2.19 to 3.07 compared to that before starting pazopanib. On day 28, his PT-INR further increased to 4.34, and his aspartate aminotransferase, alanine transaminase, and alkaline phosphatase levels increased. The target concentration of pazopanib was 20.5 to 50.3 µg/mL, but his blood concentrations were 92.1 µg/mL on day 6 and 93.7 µg/mL on day 13. Therefore, both pazopanib and warfarin were discontinued. One week later, his laboratory tests recovered, and hence, warfarin treatment was resumed. However, pazopanib therapy was terminated due to concerns about liver dysfunction. His hepatic dysfunction and increased PT-INR were considered to be due to pazopanib treatment. Pazopanib has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients. In this case, blood levels of pazopanib were abnormally high, possibly causing liver dysfunction and drug interactions, leading to his PT-INR prolongation. TDM monitoring, in addition to the recommended monitoring for pazopanib hepatotoxicity, may help identify patients at risk for drug interactions. For patients receiving concomitant pazopanib and warfarin, close monitoring of PT-INR is warranted.

DOI PubMed

Estimation of Blood Sirolimus Concentration Based on Tacrolimus Concentration/Dose Normalized by Body Weight Ratio in Lung Transplant Patients.

Masafumi Kikuchi, Kensuke Shigeta, Masaki Tanaka, Shinya Takasaki, Miki Akiba, Hisashi Oishi, Tetsu Sado, Yasushi Matsuda, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi

Therapeutic drug monitoring   41 ( 5 ) 615 - 619   2019年10月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Sirolimus and tacrolimus require accurate drug dosing based on their target blood levels to produce better clinical outcomes, specifically, the avoidance of drug-induced adverse effects and the maintenance of efficacy. However, because the ideal dose of sirolimus and the schedule for measuring its blood levels are unclear in lung transplant patients, an index is required for estimating sirolimus blood concentrations. The aim of this work is to study the correlation between the trough concentration/dose normalized by body weight (C0/D) ratios of sirolimus and tacrolimus in lung transplant patients. METHODS: Thirteen lymphangiomyomatosis patients who underwent lung transplantation and were treated with sirolimus and tacrolimus from February 2015 to July 2018 were divided into 2 groups, one receiving twice-daily (TD, n = 6) and the other once-daily (OD, n = 7) tacrolimus formulations. The correlation between the C0/D ratio of sirolimus and patient background was evaluated using Spearman's rank correlation coefficient. Correlations between sirolimus and tacrolimus C0/D ratios or doses were analyzed by single regression analysis. RESULTS: Significant correlations were found between the C0/D ratios of sirolimus and tacrolimus. The regression equations from the initial data of TD and OD groups at steady state were y = 1.880x + 32.636 (adjusted R = 0.743, P = 0.017) and y = 1.684x + 38.816 (adjusted R = 0.919, P < 0.001), respectively. In addition, the regression equations from all data of TD and OD groups were y = 1.883x + 4.170 (adjusted R = 0.546, P < 0.001) and y = 1.950x + 43.188 (adjusted R = 0.898, P < 0.001), respectively. A significant correlation between the dosage of sirolimus and tacrolimus was observed only in the OD group, with relatively low accuracy. CONCLUSIONS: Blood sirolimus concentrations can be estimated using the C0/D ratio of tacrolimus, suggesting that the C0/D ratio of tacrolimus is an index of required sirolimus dosage and the frequency of blood sirolimus concentration measurements.

DOI PubMed

Toward Personalized Cancer Therapy with Oral Molecular-targeted Agents

Hiroaki Yamaguchi, Shinya Takasaki, Masafumi Kikuchi, Yoshihide Kawasaki, Yoichi Arai, Nariyasu Mano

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN ( PHARMACEUTICAL SOC JAPAN )  139 ( 6 ) 911 - 915   2019年06月  [査読有り]

研究論文（学術雑誌）  

Oral molecular-targeted agents are used clinically for the treatment of various types of cancer. However, even when treatment is started at the dosage indicated in the medical package insert, we have experienced many cases in which treatment had to be stopped early owing to the occurrence of serious side effects or an insufficient therapeutic effect. In recent years, a wide range of studies has been conducted on the therapeutic drug monitoring (TDM) of oral molecular-targeted therapeutic agents to prevent serious side effects and maximize the therapeutic effect. In Japan, the TDM of imatinib has been covered by insurance since 2012, and the TDM of sunitinib has been covered since 2018. In contrast, tyrosine kinase inhibitors may have severe side effects, but their TDM is not covered by medical insurance. We aimed to identify a safe, highly effective chemotherapy regimen based on scientific evidence gathered from Japanese patients. We examined the relationship between the plasma concentration of drugs and clinical findings, such as side effects and treatment effects, at our hospital. In this symposium review, we introduce our results based on the treatment of patients with renal cell carcinoma.

DOI PubMed

Fundamental Study of Behaviors of In-Source Collision Induced Dissociation and Shifting the Linear Range of Calibration Curves of Various Drugs and the Metabolites Used for Therapeutic Drug Monitoring.

Maekawa M, Tsukamoto T, Takasaki S, Kikuchi M, Sato Y, Ogura J, Hayakawa Y, Yamaguchi H, Mano N

Chromatography   40 ( 2 ) 71 - 78   2019年05月  [査読有り]

研究論文（学術雑誌）