研究等業績 - 原著論文 - 菊地 正史
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Effect of isavuconazole on the concentration of tacrolimus in a patient with genotype CYP3A5*1/*3: a case report.
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 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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Masahiro WATANABE, Masamitsu MAEKAWA, Toshihiro SATO, Yu SATO, Masaki KUMONDAI, Masafumi KIKUCHI, Nariyasu MANO
CHROMATOGRAPHY ( The Society for Chromatographic Sciences ) 2024年09月
研究論文（学術雑誌）
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Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice.
Masaki Kumondai, Reika Ogawa, Nagomi Hayashi, Yurika Ishida, Hanae Oshikiri, Yuji Sato, Masafumi Kikuchi, Yu Sato, Toshihiro Sato, Masamitsu Maekawa, Nariyasu Mano
Pharmacology research & perspectives 12 ( 4 ) e1241 2024年08月
研究論文（学術雑誌）
Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β-hydroxycortisol, deoxycholic acid, and 1β-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.
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Naldemedine-induced perforation of a diverticulum in the sigmoid colon of a patient with opioid-related constipation: a case report.
Hayato Yokota, Yumiko Akamine, Mizuki Kobayashi, Takuro Kitabayashi, Misato Horie, Tentaro Endo, Takechiyo Yamada, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences 10 ( 1 ) 50 - 50 2024年08月 [査読有り]
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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Yu Sato, Hiroki Kondo, Yuji Sato, Ai Abe, Masafumi Kikuchi, Toshihiro Sato, Masaki Kumondai, Kohei Yoshikawa, Yoshihiro Hayakawa, Masamitsu Maekawa, Nariyasu Mano
Pharmaceutics 2024年08月 [査読有り]
研究論文（学術雑誌）
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Development of a simultaneous LC-MS/MS analytical method for plasma: 16 antipsychotics approved in Japan and 4 drug metabolites.
Masamitsu Maekawa, Maki Yokota, Toshihiro Sato, Yu Sato, Masaki Kumondai, Yuji Sato, Masato Suzuka, Daisuke Kobayashi, Kotaro Sakamoto, Masaki Matsuura, Masafumi Kikuchi, Hiroshi Komatsu, Kumiko Fujii, Yuji Ozeki, Hiroaki Tomita, Nariyasu Mano
Analytical sciences : the international journal of the Japan Society for Analytical Chemistry 2024年06月
研究論文（学術雑誌）
The increased risk of adverse drug reactions due to the concomitant use of antipsychotics is problematic in the treatment of schizophrenia. Therefore, the simultaneous analysis of their plasma concentrations is required. In this study, we developed a simultaneous liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for analyzing plasma antipsychotics approved in Japan for therapeutic drug monitoring (TDM) applications. First, we counted the prescriptions for 16 antipsychotics and concomitant drugs used at the Tohoku University Hospital. LC-MS/MS was used for the simultaneous analysis of 16 antipsychotics and four drug metabolites. This analysis was conducted using a combination of selected reaction monitoring mode and reversed-phase chromatography. Following the examination of the MS/MS and LC conditions, an analytical method validation test was conducted. The developed method was used to analyze plasma antipsychotic levels in patients with schizophrenia. One-third of the patients received treatment with multiple antipsychotics. Under LC-MS/MS conditions, LC separation was performed using a combination of a C18 column and ammonium formate-based mobile phases with a gradient flow. The calibration curves were optimized by adjusting the ion abundance, and 11 compounds met the criteria for intra- and inter-day reproducibility tests. Some stability test results did not meet these criteria; therefore, further investigation is required. The developed method permitted the measurement of all the plasma parameters, including concentrations above the therapeutic range. Therefore, this method may be useful in the daily TDM practice of antipsychotics.
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Association of the modified Glasgow prognostic score and prognostic nutritional index with duration of oral anamorelin administration in patients with cancer cachexia: a retrospective cohort study.
Kazuma Fujita, Yumiko Akamine, Haruka Igarashi, Yayoi Fukushi, Katsuya Sasaki, Koji Fukuda, Masafumi Kikuchi, Hiroyuki Shibata
Japanese journal of clinical oncology 2024年06月 [査読有り]
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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Case report of QT interval prolongation induced by anamorelin in an obese patient with non-small cell lung cancer.
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 10 ( 1 ) 33 - 33 2024年06月 [査読有り]
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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Toshihiro Sato, Ayaka Yagi, Minami Yamauchi, Masaki Kumondai, Yu Sato, Masafumi Kikuchi, Masamitsu Maekawa, Hiroaki Yamaguchi, Takaaki Abe, Nariyasu Mano
International Journal of Molecular Sciences 2024年01月
研究論文（学術雑誌）
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多職種協働による最適ながん薬物療法の開発
菊地正史
秋田医学 51 ( 1 ) 29 - 36 2024年
研究論文（学術雑誌）
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Plasma Venetoclax Concentrations in Patients with Acute Myeloid Leukemia Treated with CYP3A4 Inhibitors.
Ayaka Otsuki, Masaki Kumondai, Daisuke Kobayashi, Masafumi Kikuchi, Yugo Ueki, Yuji Sato, Nagomi Hayashi, Ayaka Yagi, Yasushi Onishi, Koichi Onodera, Satoshi Ichikawa, Noriko Fukuhara, Hisayuki Yokoyama, Masamitsu Maekawa, Nariyasu Mano
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 144 ( 7 ) 775 - 779 2024年
研究論文（学術雑誌）
Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.
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簡易懸濁法を用いて在宅でオシメルチニブを経管投与した非小細胞肺癌の一例
水口敦史, 菊地正史, 成田佳奈, 宮内栄作, 眞野成康
医薬品相互作用研究 48 ( 1 ) 18 - 23 2024年 [査読有り]
研究論文（学術雑誌）
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Keitaro Miyoshi, Eiji Hishinuma, Naomi Matsukawa, Yoshitaka Shirasago, Masahiro Watanabe, Toshihiro Sato, Yu Sato, Masaki Kumondai, Masafumi Kikuchi, Seizo Koshiba, Masayoshi Fukasawa, Masamitsu Maekawa, Nariyasu Mano
International Journal of Molecular Sciences ( MDPI AG ) 24 ( 21 ) 15642 - 15642 2023年10月
研究論文（学術雑誌）
Niemann–Pick disease type C (NPC) is an autosomal recessive disorder with progressive neurodegeneration. Although the causative genes were previously identified, NPC has unclear pathophysiological aspects, and patients with NPC present various symptoms and onset ages. However, various novel biomarkers and metabolic alterations have been investigated; at present, few comprehensive proteomic alterations have been reported in relation to NPC. In this study, we aimed to elucidate proteomic alterations in NPC and perform a global proteomics analysis for NPC model cells. First, we developed two NPC cell models by knocking out NPC1 using CRISPR/Cas9 (KO1 and KO2). Second, we performed a label-free (LF) global proteomics analysis. Using the LF approach, more than 300 proteins, defined as differentially expressed proteins (DEPs), changed in the KO1 and/or KO2 cells, while the two models shared 35 DEPs. As a bioinformatics analysis, the construction of a protein–protein interaction (PPI) network and an enrichment analysis showed that common characteristic pathways such as ferroptosis and mitophagy were identified in the two model cells. There are few reports of the involvement of NPC in ferroptosis, and this study presents ferroptosis as an altered pathway in NPC. On the other hand, many other pathways and DEPs were previously suggested to be associated with NPC, supporting the link between the proteome analyzed here and NPC. Therapeutic research based on these results is expected in the future.
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High throughput LC/ESI-MS/MS method for simultaneous analysis of 20 oral molecular-targeted anticancer drugs and the active metabolite of sunitinib in human plasma
Tensei Hirasawa, Masafumi Kikuchi, Shinya Takasaki, Masaki Kumondai, Yu Sato, Toshihiro Sato, Eishi Imoto, Yoshihiro Hayakawa, Masamitsu Maekawa, Nariyasu Mano
Heliyon ( Elsevier BV ) 9 ( 6 ) e16926 - e16926 2023年06月 [査読有り]
研究論文（学術雑誌）
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The prevalence of end-of-life chemotherapy and targeted therapy in Japan, assessed using a health claims database.
Masami Tsuchiya, Taku Obara, Masafumi Kikuchi, Nariyasu Mano
Cancer chemotherapy and pharmacology 2023年05月 [査読有り]
研究論文（学術雑誌）
PURPOSE: This study aimed to investigate the current status of end-of-life chemotherapy and targeted therapy and explore the aggressiveness of end-of-life care in Japan using the DeSC database, a large administrative claims database. METHODS: We identified fatal cases of at least one cancer-related diagnosis between April 2015 and November 2020. Patients prescribed at least one anticancer drug were analyzed, and chemotherapy regimens were categorized based on the combination of concomitant anticancer drugs prescribed. RESULTS: Among 1,095,713 individuals enrolled in the National Health Insurance database, 7,300 deaths with cancer-related diagnosis were identified. Of these, 4,010 cases were identified in which at least one anticancer drug was prescribed, and 11.6% of 7,300 death had been prescribed anticancer drugs in their last 30 days of life. The most commonly used regimen was S-1 (tegafur, gimeracil, and oteracil potassium combination) monotherapy, followed by nivolumab monotherapy and nab-paclitaxel plus gemcitabine. Immune checkpoint inhibitor monotherapy was more likely prescribed to patients whose last chemotherapy dose was in the last 30 days of life (p = 0.0066, chi-squared test). CONCLUSIONS: This study provides insights into the current status of end-of-life chemotherapy and targeted therapy in Japan, using a large administrative claims database. The results of this study will inform future research on end-of-life chemotherapy and targeted therapy, and help develop strategies to improve the quality of life of patients with advanced cancer.
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Masaki Kumondai, Masamitsu Maekawa, Eiji Hishinuma, Yu Sato, Toshihiro Sato, Masafumi Kikuchi, Masahiro Hiratsuka, Nariyasu Mano
Biological and Pharmaceutical Bulletin ( Pharmaceutical Society of Japan ) 46 ( 3 ) 455 - 463 2023年03月 [査読有り]
研究論文（学術雑誌）
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Therapeutic Drug Monitoring of Blood Sirolimus and Tacrolimus Concentrations for Polypharmacy Management in a Lymphangioleiomyomatosis Patient Taking Two Cytochrome P450 3A Inhibitors.
Masaki Kumondai, Masafumi Kikuchi, Atsushi Mizuguchi, Nagomi Hayashi, Masahiro Ui, Takashi Hirama, Yoshinori Okada, Yu Sato, Toshihiro Sato, Masamitsu Maekawa, Nariyasu Mano
The Tohoku journal of experimental medicine 260 ( 1 ) 29 - 34 2023年03月 [査読有り]
研究論文（学術雑誌）
Patients with lymphangioleiomyomatosis (LAM) and lung transplantations are treated with multiple drugs, such as tacrolimus, mycophenolate mofetil, prednisolone, and itraconazole, for long-term suppression of rejection response and prevention of infection. Additional drugs are required when lung transplant recipients develop graft complications. Therefore, managing polypharmacy is critical because of drug-drug interactions caused by various factors, including drug-metabolizing enzymes such as cytochrome P450 3A (CYP3A). The patient was a 48-year-old woman (height 144.9 cm and weight 38.4 kg) who underwent lung transplantation for LAM. Mycophenolate mofetil, tacrolimus (target blood concentration, 4.0-8.0 ng/mL), and prednisolone were administered for immunosuppression, and itraconazole and clarithromycin were administered to manage graft infection. The patient developed unilateral lymphedema, predominantly in the left leg; therefore, sirolimus was initiated with a target blood concentration of 3.0-5.0 ng/mL. In addition to 1.0 mg/day of sirolimus, tacrolimus (0.3 mg/day), itraconazole (100 mg/day), and clarithromycin (800 mg/day) were added. Blood sirolimus concentrations ranged from 18.8 to 36.9 ng/mL on days 6 to 9; thus, treatment with sirolimus was stopped because of over-target blood concentrations. Blood concentrations of sirolimus and tacrolimus were successfully managed without adverse events using therapeutic drug monitoring (TDM) and azole anti-fungal substitution of azithromycin instead of clarithromycin although sirolimus concentration was relatively lower compared to the target range. Thereby, frequent TDM, management of polypharmacy that influences CYP3A activity, and possibly CYP3A genotyping should be appropriately conducted for personalized medicine.
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Kentaro Tajima, Tomofumi Ishikawa, Masami Tsuchiya, Masafumi Kikuchi, Taku Obara, Nariyasu Mano
Pharmacoepidemiology 2023年01月 [査読有り]
研究論文（学術雑誌）
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Evaluation of a Capillary Microsampling Device for Analyzing Plasma Lenvatinib Concentration in Patients With Hepatocellular Carcinoma.
Akihiro Saito, Masafumi Kikuchi, Yuko Matsumoto, Erina Sugawara, Gesshu Takao, Hayato Inomata, Akane Takahashi, Yuji Sato, Masaki Kumondai, Yu Sato, Toshihiro Sato, Masashi Ninomiya, Jun Inoue, Masamitsu Maekawa, Nariyasu Mano
Therapeutic drug monitoring 44 ( 6 ) 771 - 776 2022年12月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: The anticancer drug, Lenvima (lenvatinib), has severe side effects. Therapeutic drug monitoring helps ensure its efficacy and safety. Regular and optimally timed blood sampling is tough, especially when lenvatinib is self-medicated. Microsampling using the easy to handle Microsampling Wing (MSW) may help circumvent this problem. However, current lenvatinib detection methods are not sensitive enough to detect its concentrations in microsamples (<50-250 μL). Thus, the aim of this study was 2-fold (1) develop an analytic method to estimate plasma lenvatinib concentrations in microsamples and (2) verify whether this method works on micro (5.6 μL) blood plasma samples obtained clinically through MSW from patients with unresectable hepatocellular carcinoma (HCC). METHODS: A simple, highly sensitive, and specific liquid chromatography-electrospray ionization tandem mass spectrometry method was developed. Using this novel protocol, the trough blood plasma concentration of lenvatinib was measured for both blood sampled conventionally and that using MSW. Thirty-five venous whole blood samples were obtained from 11 patients with HCC. Furthermore, the stability of lenvatinib in MSW samples during storage was evaluated. RESULTS: The mean plasma lenvatinib concentration estimates were not significantly different between the MSW and conventional venous blood samples. CV for interday and intraday assays was low. Up to day 5, the lenvatinib concentration in the MSW samples was 85%-115% of the initial day concentration (when stored at 25°C or 4°C). The interference of endogenous matrix components in the human plasma was low. CONCLUSIONS: These results indicate that the novel mass spectrometry protocol accurately measures lenvatinib in human plasma and is reproducible. Thus, MSW could be a useful microsampling device for lenvatinib therapeutic drug monitoring in patients with HCC when used in combination with this novel liquid chromatography-electrospray ionization tandem mass spectrometry detection method.
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Masamitsu Maekawa, Keitaro Miyoshi, Aya Narita, Toshihiro Sato, Yu Sato, Masaki Kumondai, Masafumi Kikuchi, Katsumi Higaki, Torayuki Okuyama, Yoshikatsu Eto, Hiroshi Sakamaki, Nariyasu Mano
Biological and Pharmaceutical Bulletin ( Pharmaceutical Society of Japan ) 45 ( 9 ) 1259 - 1268 2022年09月 [査読有り]
研究論文（学術雑誌）
As Niemann-Pick disease type C (NPC) is difficult to diagnose owing to its various clinical symptoms; biomarker tests have been developed. Previously, we revealed urinary sulfated cholesterol metabolites as noninvasive biomarkers for NPC. However, LC/tandem mass spectrometry (LC/MS/MS) requires long separation time and large urine volumes. Recently, a basic mobile phase was reported to increase the MS intensity. Thus, we developed a highly sensitive and rapid LC/MS/MS method for analyzing urinary cholesterol metabolites using a basic mobile phase additive. 3β-Sulfooxy-7β-N-acetylglucosaminyl-5-cholenic acid, its glycine and taurine conjugates, 3β-sulfooxy-7β-hydroxy-5-cholenic acid, and 7-oxo form were measured, with selected reaction monitoring in negative ion mode. Oasis HLB and L-column 3 were used for column-switching LC/MS/MS and urine diluted 10-fold was employed as the sample. After trapping, gradient separation was performed using solutions containing 1% (v/v) ammonium solution. On average, a 16-fold increase in peak areas was observed compared to that obtained at pH 5.5 with the mobile phases. Although the previous method needed 60 min for separation from interference peaks, we succeeded to separate them in 7 min with optimized LC condition. Further, all compounds showed good linearity from 0.3-1000 ng/mL, with satisfactory intra- and inter-day reproducibility. The developed method was applied to the urinalysis of healthy participants and NPC patients. Overall, the concentrations of metabolites correlated with those obtained using the previous method. Therefore, we succeeded to increasing MS intensity and shorten LC running time; and the method is useful for the noninvasive diagnostic screening of patients with NPC.