研究者詳細 - 藤田　有美

藤田　有美（フジタ　アリミ）

Fujita, Arimi

写真a

所属（所属キャンパス）: 薬学部薬学科（芝共立）

職名: 助教

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経歴【表示／非表示】

2019年10月

-

2026年03月

金沢大学, 附属病院, 特任助教

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Neonatal hypoglycemia triggered by maternal ritodrine administration is caused by inhibition of gluconeogenesis in the neonatal liver in rodents

Kajino M., Fujita A., Nishizawa R., Shimokawa S., Kawakami T., Inaba Y., Shimada T., Inoue H., Sai Y.

Biochemical and Biophysical Research Communications 795 2026年01月

ISSN 0006291X

　概要を見る

Neonatal hypoglycemia, a known risk factor for neurodevelopmental impairment, may result from maternal exposure to ritodrine, a β<inf>2</inf>-adrenergic agonist used as a tocolytic agent to prevent preterm labor. We established a rodent model of ritodrine-induced neonatal hypoglycemia to elucidate mechanisms underlying this adverse effect. Ritodrine administration to pregnant rodents (dams) significantly decreased plasma glucose levels in their offspring (pups) 3 h after birth, compared with the phosphate-buffered saline (PBS) group. Although plasma insulin concentrations were significantly lower in the ritodrine group at birth, no significant differences were observed thereafter, suggesting this hypoglycemia is insulin-independent. Since blood glucose levels are regulated by a balance between peripheral glucose utilization and hepatic glucose production, we first assessed peripheral glucose uptake by measuring 2-deoxyglucose incorporation in the pup limbs. No significant differences were observed between the ritodrine and PBS groups. We next investigated whether the observed hypoglycemia was due to impaired hepatic glucose production. Hepatic glycogen content at birth was comparable between the two groups. Liver-targeted metabolomic analysis revealed that the rapid decline in gluconeogenesis (GNG)-related metabolites seen between 2 and 3 h after birth in the PBS group was absent in the ritodrine group. Furthermore, during GNG substrate tolerance tests, pups in the ritodrine group exhibited significantly lower blood glucose levels than those in the PBS group. Finally, hepatic expression of genes encoding gluconeogenic enzymes was significantly reduced in the ritodrine group. Overall, our findings demonstrate that ritodrine-induced neonatal hypoglycemia is caused by suppression of hepatic gluconeogenic enzyme expression in an insulin-independent manner.
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Drug-drug interaction between trastuzumab emtansine (T-DM1) and orally administered tacrolimus in a patient and in rats

Nakamura T., Shimada M., Takabayashi M., Fujita A., Kawakami T., Maruyama H., Terakawa H., Ishimoto T., Shimada T., Miyamoto T., Sai Y.

Drug Metabolism and Pharmacokinetics 62 2025年06月

ISSN 13474367

　概要を見る

We have experienced a 2.3-fold increase in the trough concentration of orally administered tacrolimus in a patient for 7 days after intravenous administration of trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Retrospective clinical study revealed no change in factors known to alter the pharmacokinetics of tacrolimus, and the change in the trough concentration of tacrolimus was reversed after switching T-DM1 to trastuzumab (Tmab). Thus, interaction with T-DM1 was suspected as the cause of the increased trough concentration of tacrolimus. An animal study in rats showed that T-DM1 significantly increased the AUC<inf>0-∞</inf> of orally administered tacrolimus by more than 2-fold on day 0, day 3, and day 7, whereas no change was observed in the case of intravenous administration of tacrolimus. T-DM1 also significantly increased F<inf>a</inf>・F<inf>g</inf> of tacrolimus by more than 2-fold on day 7. In contrast, Tmab itself had no effect on the blood concentration of tacrolimus. These results suggest that T-DM1 increased the blood concentration of orally administered tacrolimus, and the effect persisted for 1 week after T-DM1 administration. Metabolites of T-DM1 excreted via the biliary route may contribute to the increase in the gastrointestinal absorption of tacrolimus.
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Effect of obesity on pharmacokinetics of transdermal fentanyl: Single-center retrospective study and animal study

Mizuno S., Gake S., Takabayashi M., Ito Y., Sanada H., Sugimoto N., Maeda A., Tamamura T., Sawamoto K., Hara Y., Ohi Y., Tsuji C., Shiomoto Y., Kato Y., Fujita A., Shimada T., Miyamoto K.i., Sai Y.

Drug Metabolism and Pharmacokinetics 60 2025年02月

ISSN 13474367

　概要を見る

A retrospective study and an animal study were conducted to investigate factors affecting the transdermal fentanyl dose to achieve adequate pain relief in patients switched from other opioids. In the retrospective study, patient factors were included as gender, age, body mass index (BMI), and serum albumin concentration. In obese (BMI ≥25) patients, the post-titration dose of transdermal fentanyl was significantly lower than in normal (BMI 18.5–25) patients despite the initial dose was the same. To support this unexpected finding, fentanyl was administered intravenously and transdermally to Zucker (fa/fa) rats as an obese model and Zucker (+/+) rats as a control. No difference in systemic clearance (CL<inf>tot</inf>) after intravenous administration was observed between the two groups. However, transdermal bioavailability (F) and fentanyl release ratio from the formulation (F<inf>a</inf>) were significantly increased in Zucker (fa/fa) rats compared to Zucker (+/+) rats. Skin availability (F<inf>skin</inf>), calculated as F divided by F<inf>a</inf>, was also significantly increased. These results indicated that obesity should be considered as a factor in the titration of transdermal fentanyl dose.
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Effect of changes in skin properties due to diabetes mellitus on the titration period of transdermal fentanyl: single-center retrospective study and diabetic animal model study

Mizuno S., Takabayashi M., Makihara H., Ogai K., Tsukui K., Ito Y., Kawakami T., Hara Y., Fujita A., Tokudome Y., Akase T., Kato Y., Shimada T., Sai Y.

Journal of Pharmaceutical Health Care and Sciences 10 （ 1 ） 2024年12月

　概要を見る

Background: In the dose titration of transdermal fentanyl to prevent unrelieved pain, it is important to consider not only dose adjustment, but also the titration period, which is influenced by the time required to reach the steady state. Many patients with cancer pain experience comorbidities that might affect the skin properties and influence transdermal absorption. We hypothesized that skin changes due to diabetes mellitus (DM) would affect the titration period of transdermal fentanyl. We conducted a retrospective study and diabetic animal model study to test this hypothesis. Methods: In the retrospective study, the titration period was defined in terms of “dose change” and “number of rescue opioids” in patients initiated on transdermal fentanyl. Multiple logistic regression analysis was performed to analyze the relation between the titration period and comorbidities, including DM. In the diabetic animal model study, intercellular lipids of stratum corneum (SC) were analyzed in Goto-Kakizaki (GK) rats, a model of DM, and the pharmacokinetics of intravenously or transdermally administered fentanyl was examined. Results: In the retrospective study, the titration period ranged from 5 to 39 days (n = 387), and the patients taking a longer period (6 days or more) was significantly related to in patients with unspecified DM: AOR (95% confidence interval), 0.438 (0.217–0.884). In the diabetic animal model study, the ceramides (CERs) content in the SC was decreased by approximately 30% in GK rats compared to Wistar rats. The absorption rate constant (k<inf>a</inf>) of fentanyl administered transdermally was increased approximately 1.4-fold in GK rats, though there was no difference in transdermal bioavailability (F) or systemic clearance (CL<inf>tot</inf>). Conclusion: Our results suggest that the steady state of transdermally administered fentanyl is reached sooner in cancer patients with DM as a comorbidity. Earlier pain assessment and dose adjustment may be possible in these patients.
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Validation of an automated sample preparation module directly connected to LC-MS/MS (CLAM-LC-MS/MS system) and comparison with conventional immunoassays for quantitation of tacrolimus and cyclosporin A in a clinical setting

Shimada T., Kawakami D., Fujita A., Yamamoto R., Hara S., Ito K., Mizushima I., Kitajima S., Iwata Y., Sakai N., Kawano M., Wada T., Sai Y.

Journal of Pharmaceutical Health Care and Sciences 10 （ 1 ） 2024年12月

　概要を見る

Background: Therapeutic drug monitoring (TDM) systems generally use either liquid chromatography/tandem mass spectrometry (LC-MS/MS) or immunoassay, though both methodologies have disadvantages. In this study, we aimed to evaluate whether a CLAM-LC-MS/MS system, which consists of a sample preparation module directly connected to LC-MS/MS, could be used for clinical TDM work for immunosuppressive drugs in whole blood, which requires a hemolytic process. For this purpose, we prospectively validated this system for clinical measurement of tacrolimus and cyclosporin A in patients’ whole blood. The results were also compared with those of commercial immunoassays. Methods: Whole blood from patients treated with tacrolimus or cyclosporin A at the Department of Nephrology and Departments of Rheumatology, Kanazawa University Hospital, from May 2018 to July 2019 was collected with informed consent, and drug concentrations were measured by CLAM-LC-MS/MS and by chemiluminescence immunoassay (CLIA) for tacrolimus and affinity column-mediated immunoassay (ACMIA) for cyclosporin A. Correlations between the CLAM-LC-MS/MS and immunoassay results were analyzed. Results: Two hundred and twenty-four blood samples from 80 patients were used for tacrolimus measurement, and 76 samples from 21 patients were used for cyclosporin A. Intra- and inter-assay precision values of quality controls were less than 7%. There were significant correlations between CLAM-LC-MS/MS and the immunoassays for tacrolimus and cyclosporin A (Spearman rank correlation coefficients: 0.861, 0.941, P < 0.00001 in each case). The drug concentrations measured by CLAM-LC-MS/MS were about 20% lower than those obtained using the immunoassays. CLAM-LC-MS/MS maintenance requirements did not interfere with clinical operations. Compared to manual pretreatment, automated pretreatment by CLAM showed lower inter-assay precision values and greatly reduced the pretreatment time. Conclusions: The results obtained by CLAM-LC-MS/MS were highly correlated with those of commercial immunoassay methods. CLAM-LC-MS/MS offers advantages in clinical TDM practice, including simple, automatic pretreatment, low maintenance requirement, and avoidance of interference.
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