Ikuto Tsukiyama

Aichi Medical University, Koromo, Aichi, Japan

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Publications (12)15.15 Total impact

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    ABSTRACT: We investigated whether hepatic multidrug resistance-associated protein 2 (ABCC2) is involved in the hepatobiliary excretion of regorafenib, a novel multi-kinase inhibitor, using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR) lacking the efflux transporter ABCC2. The involvement of organic anion-transporting polypeptide 1 (OATP1; OATP in humans) and OATP2 in the hepatic uptake of regorafenib and their protein levels in the liver were also investigated in the two rat groups. When regorafenib (5 mg/kg) was administered intravenously, the plasma concentrations of regorafenib were higher in EHBR than those in SD rats. However, the slope of the plasma concentration-time curves was the same for the two groups. Although the apparent biliary clearance of regorafenib in EHBR was lower than that of SD rats, no significant difference in the biliary excretion rate was observed between them, suggesting that regorafenib is not a substrate for ABCC2 and is not excreted into bile by ABCC2. It was also found that the contribution of biliary excretion to the systemic elimination of regorafenib is small. The protein-binding profiles of regorafenib were found to be linear in both rat groups. The binding potency, which was very high in both rat groups (>99.5%), was significantly higher in EHBR than that in SD rats. No significant differences in the plasma concentrations of unbound regorafenib were observed between the two rat groups, suggesting that the differences observed in the pharmacokinetic behaviors of regorafenib between the two rat groups were due to differences in protein-binding. When the protein levels of hepatic OATP1 and OATP2 were measured by immunoblot analysis, the expression of both transporters in EHBR was less than 40% of that in SD rats. The present results suggest that regorafenib is not a substrate for OATP1 and OATP2. These findings suggest the possibility that ABCC2-mediated hepatobiliary excretion and OATP1/OATP2-mediated hepatic uptake do not play important roles in the disposition of regorafenib. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
    No preview · Article · Sep 2015 · Anticancer research
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    Takumi Takano · Shigeru Suzuki · Ikuto Tsukiyama · Hiroko Saito
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    ABSTRACT: Anti-cancer drugs are harmful to healthy persons. In recent years, occupational exposure to anti-cancer drugs has become a major concern to health care workers. To address this issue, a smear method was developed to measure widely using anti-cancer drugs depositing on the floors, safety cabinet surfaces, and tables in hospital. Ten kinds of widely used anti-cancer drugs, paclitaxel, vincristine, docetaxel, vinorelbine, irinotecan, methotrexate, oxaliplatin, cyclophosphamide, gemcitabine and fluorouracil were collected by smearing material surfaces with methanol impregnated cellulose filter paper and/or polypropylene nonwoven. The collected anti-cancer drugs are extracted in 5 ml of 0.01% (v/v) hydrazine/methanol solution by sonication. The extracted solution was filtered and concentrated to prepare 1 ml of sample solution. Then, the anti-cancer drugs in the sample solution were simultaneously measured by LC/MS. The anti-cancer drugs excepting fluorouracil spread on P-tile surface were measured with recoveries of 37~101% and standard deviations (SD) of 1.8~19%. All 10 of the anti-cancer drugs on a stainless steel plate surface were measured with the recoveries of 35~111% and SD of 1.3~11%. Using this smear method, 9 or 10 kinds of widely used anti-cancer drug residues in hospital, possibly exposed to health care workers, were grasped.
    Preview · Article · Aug 2015 · Sangyo eiseigaku zasshi Journal of occupational health
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    ABSTRACT: The present study aimed to assess the efficacy of 15 mEq magnesium supplied as part of a prehydration regimen in preventing cisplatin-induced nephrotoxicity in patients undergoing therapy with cisplatin-alone (40 mg/m(2)/week) for cervical cancer. We studied 28 patients with cervical cancer. This prospective cohort study compared nephrotoxicity in patients who received hydration with and without magnesium sulfate (Mg-hydration group, n=14; non-Mg-hydration group, n=14). Baseline characteristics, stage of cervical cancer, cisplatin dose and renal function did not differ significantly between the two groups. The serum creatinine level significantly increased from 0.58 to 0.75 mg/dl, and the estimated glomerular filtration rate significantly decreased from 85.1 to 66.5 ml/min by chemotherapy in the non-Mg-hydration group. In contrast, these levels did not change significantly in the Mg-hydration group. A magnesium dose of 15 mEq was found to provide nephroprotective effects among patients with cervical cancer undergoing chemotherapy with cisplatin alone. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
    No preview · Article · Apr 2015 · Anticancer research
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    ABSTRACT: Purpose: Neurokinin-1 (NK-1) receptor antagonist is recommended for chemotherapy-induced nausea and vomiting (CINV) in highly emetogenic chemotherapy (HEC) and has recently been introduced to oncology practice in Japan. However, whether all patients undergoing HEC truly need NK-1 receptor antagonist remains unknown, and increasing medical costs due to uniform use of NK-1 receptor antagonist are a concern. This study was conducted to examine the prevalence of patients who needed aprepitant at the time of its introduction in Japan, and therapeutic and preventive effects of aprepitant on HEC or moderately emetogenic chemotherapy (MEC). Patients and methods: Eligible patients with thoracic malignancies who were to undergo HEC or MEC received 5-hydroxytryptamine receptor antagonists and dexamethasone to prevent CINV. Aprepitant was administered to treat CINV occurring in the first course, or to prevent CINV in the second course. Frequency of vomiting, degree of nausea, and quality of life with respect to CINV were assessed. Results: In total, 96 patients were enrolled. Aprepitant was not administered in 57 and 88 % of patients who received HEC and MEC, respectively. In patients treated with aprepitant (n = 18), therapeutic use of aprepitant after occurrence of CINV (n = 9) decreased average scores in numerical rating scale for nausea from 7.44 to 5.44 (p = 0.10), and average frequency of vomiting per day from 2.11 to 0.11 (p = 0.03). Prophylactic use of aprepitant in the second course (n = 18) increased the proportion of patients with no significant nausea from 6 % (first course) to 50 % (second course; p = 0.007), and those with no vomiting from 33 to 89 % (p = 0.002). Aprepitant use also significantly improved quality of life with respect to CINV in the second course. Conclusion: More than half of patients receiving HEC and 88 % of patients receiving MEC did not use aprepitant. Aprepitant showed significant therapeutic and preventive effects on CINV in patients who truly needed it.
    No preview · Article · Sep 2014 · Supportive Care Cancer
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    ABSTRACT: The present study investigated the role of the major plasma proteins, albumin and α1-acid glycoprotein (AAG), in the pharmacokinetics of sunitinib using Sprague-Dawley (SD) rats and analbuminemic rats with considerably low concentration of albumin established from SD rats. When sunitinib (3 mg/kg) was administered intravenously, the plasma concentrations of sunitinib at the early-distribution phase were significantly lower in analbuminemic rats than those in SD rats. The corresponding pharmacokinetic parameters of systemic clearance and volume of distribution at steady-state of sunitinib were significantly larger in analbuminemic rats (2.17 l/h/kg and 3.94 l/kg, respectively) than those in SD rats (1.26 l/h/kg and 2.37 l/kg, respectively). In in vitro protein-binding experiments using an equilibrium dialysis method, the binding profiles of sunitinib in SD and analbuminemic rats were linear, and the unbound fraction in analbuminemic rats (0.110) was significantly larger than that of SD rats (0.062). However, no significant differences in the unbound plasma concentration-time curves and pharmacokinetic parameters of sunitinib were observed between SD and analbuminemic rats. Protein-binding profiles of sunitinib to human serum albumin and AAG showed concentration independency and the binding potency was 65.3% and 33.7%, respectively. These results suggest that AAG has a low affinity for sunitinib and that the contribution of AAG to plasma protein-binding of sunitinib is relatively low compared to albumin. The present study suggests that the increased systemic clearance of sunitinib in analbuminemic rats might be due to an increase in the volume of distribution at steady-state, which could be due to the significant increase in the unbound fraction of sunitinib due to the low concentration of albumin.
    No preview · Article · May 2014 · Anticancer research
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    ABSTRACT: Patients with progressive renal cell carcinoma who undergo sunitinib treatment, experience many adverse events (AEs), including thrombopenia and hypertension. Dose reduction or treatment discontinuation due to AEs makes it difficult to control the clinical condition. Therefore, patients' understanding regarding the basics of blood pressure (BP) measurement and how to deal with each AE are particularly important. Here we report whether or not pharmacist instructions help in order to increase patients' awareness of early AE management results in an improvement of treatment outcomes. The present study included 15 patients who were administered sunitinib. From the start of sunitinib treatment, pharmacists continuously provided drug administration guidance to the patients and confirmed their awareness and knowledge regarding AEs, symptom management, and drug adherence. The relative dose intensity (RDI) of 15 patients from week 1 to 24 after sunitinib treatment was calculated. Pharmaceutical interventions significantly improved patients' understanding of BP measurements and reference values, etc. Although the RDI was 67.3%-78.7%, there were no cases of discontinuation of administration or reduction of the dose caused by e.g. hypertension, hand and foot syndrome (HFS) and stomatitis. Pharmaceutical interventions improved patients' awareness of the management of AEs and adherence to sunitinib therapy. As a result, a high RDI was maintained, which may lead to prolonged survival. Therefore, our results suggest that early AE management provided by pharmacists is particularly important to assure the safety and efficacy of sunitinib therapy.
    No preview · Article · Nov 2013 · Anticancer research
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    ABSTRACT: The present study investigated the effect of the H2 antagonist cimetidine on the pharmacokinetics of a multi-targeted receptor tyrosine kinase (RTK) inhibitor, sunitinib, in Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic mutant rats (EHBR) lacking the efflux transporter, ATP-binding cassette C2 protein (ABCC2). Rats received an intraperitoneal injection of cimetidine (10 mg/kg) once a day for three days. On day 4, sunitinib (3 mg/kg) was administered intravenously 30 min after the final injection of cimetidine or saline to SD rats. Disappearance of sunitinib from plasma was significantly delayed by cimetidine. The pharmacokinetic parameter of sunitinib, systemic clearance (CLSYS), was significantly reduced and the half-life was significantly prolonged, with no change in the volume of distribution at steady-state (VSS). When the effect of cimetidine on the biliary excretion of sunitinib at steady-state condition was investigated in SD rats, cimetidine had no effect on some transporter-mediated biliary excretion of sunitinib. Furthermore, the contribution of ABCC2 to the biliary excretion of sunitinib was also examined in SD rats and EHBR. The biliary clearance of sunitinib was significantly lower in EHBR, but the biliary excretion rate of EHBR was not different from that of SD rats, and the contribution of biliary excretion to systemic elimination was small, suggesting that sunitinib is mainly eliminated by cytochrome P450 3A4 (CYP3A4)-mediated metabolism and is not excreted into the bile via ABCC2. These findings indicate that co-administration of cimetidine alters the pharmacokinetics of sunitinib probably due to inhibition of CYP3A4, suggesting the possibility that cimetidine should be used carefully for patients with cancer being treated with sunitinib therapy.
    No preview · Article · Aug 2013 · Anticancer research
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    ABSTRACT: Onetaxotere®(OTAX)injection, which is a docetaxel(DOC)injection formulation, cannot be administered to those patients with alcohol intolerance or hypersensitivity, because it contains ethanol as a dissolving agent. To broaden treatment options for those patients, we tried to eliminate ethanol from OTAX injection. Under sterile conditions, dealcoholization was carried out using nitrogen gas in a hot water bath at 50°C. By this method, the ethanol included in OTAX injection was almost completely removed and DOC in the formulation was stable for 28 days. When the dealcoholized or untreated OTAX injection was intravenously injected in rats, no significant differences in the pharmacokinetic parameters of DOC were observed between those with dealcoholized and untreated OTAX injections. It is expected that dealcoholized OTAX may be useful in patients with alcohol-related difficulties.
    No preview · Article · Jul 2013 · Gan to kagaku ryoho. Cancer & chemotherapy
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    ABSTRACT: A 39-year-old woman with advanced and recurrent cervical carcinoma received chemotherapy with IFM+CDDP(IFM 5, 000mg/m2 by intravenous infusion for 24 hours and CDDP 50 mg/m2 by intravenous infusion for one hour)in September of 2011. Mesna(3, 200mg/body)was administered intravenously for 30min three times a day to prevent IFM-induced hemorrhagic cystitis. She complained of residual urine from the evening of day 2 and felt pain during urination from day 3 (urinary tract pain: Grade 1 CTCAE v4.0 ). Both symptoms continued until day 6. When the infusion rate of mesna was changed to 24 hours of continuous administration, as with IFM on the second course, no symptoms which occurred during the first course were observed. The chemotherapy could be continued without compromising her QOL. The present finding suggests that IFM-induced dysuria could be avoided by changing the regimen to mesna, due to the increase in its binding potency and the metabolite of IFM, acrolein.
    No preview · Article · Mar 2013 · Gan to kagaku ryoho. Cancer & chemotherapy
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    ABSTRACT: The introduction of generic drugs is a favored strategy in reducing medical costs, but some clinicians are often reluctant to use them because of lack of information with regard to their side effects. Generic paclitaxel [NK] differs from the proprietary version, Taxol®, in containing added citric acid and a more pure form of castor oil. However, little information exists regarding the effects of these additives on adverse events such as vascular pain, phlebitis, hypersensitivity and hepatic dysfunction. To compensate for this lack of information and to validate the safety of using generic paclitaxel, we investigated adverse events in response to generic paclitaxel [NK]. Our investigation focused on patients treated with both the proprietary formulation (Taxol® for injection) and the generic version(paclitaxel [NK] for injection)sequentially from April 2008 to March 2009. Adverse events were investigated retrospectively. Incidence of vascular pain, phlebitis and hypersensitivity was similar to that with the original product. Although the expression of some liver enzymes was slightly increased and some gastrointestinal events were reduced following generic paclitaxel [NK] treatment there was no statistically significant difference. The profiles of other adverse events were not significantly different. Increased vascular pain and phlebitis, predicted due to low pH conditions caused by citric acid, were not observed. Similarly, the pure castor oil included in generic paclitaxel [NK] did not influence hypersensitivity and hepatic function. We found no significant differences in our study of proprietary and generic paclitaxel [NK]. Thus, clinicians have no reason for prejudice against using generic paclitaxel [NK] on the basis of increased risk of side effects.
    No preview · Article · Apr 2012 · Gan to kagaku ryoho. Cancer & chemotherapy
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    ABSTRACT: A generic drug of Taxol® Injection, Paclitaxel Injection NK (PTX injection), cannot be used for patients with severe hypersensitivity or overwhelming intolerance to alcohol because it contains ethanol as a dissolving agent. Therefore, we evaluated the suitability of de-alcoholized PTX injection for clinical application. De-alcoholization was carried out using inactive N2 gas under sterile conditions. The pharmacokinetic properties of the de-alcoholized PTX injection were evaluated in rats after intravenous injection. Finally, the de-alcoholized PTX injection was administered to a patient with alcohol intolerance to evaluate its suitability for clinical application. The ethanol included in the supplied PTX injection was almost completely removed (>99.9%). PTX, the major component of the de-alcoholized PTX injection, was stable with no decomposed compounds or bacterial contamination, although its viscosity was increased by 29-fold compared with untreated PTX injection. No significant differences in the pharmacokinetic parameters of PTX were observed between the de-alcoholized and untreated PTX injections. No drunkenness was observed in the patient with severe alcohol intolerance after injection of de-alcoholized PTX injection. Adverse events such as nausea, muscle pain, joint pain, neuropathy and myelosuppression were observed at similar degrees to those after injection of untreated PTX injection. The plasma concentrations of PTX after injection of the de-alcoholized PTX injection were similar to those after injection of untreated PTX injection. The present findings suggest that almost complete de-alcoholization of PTX can be achieved easily under sterile conditions and that the resulting product can be used safely for patients with severe alcohol intolerance.
    No preview · Article · Dec 2011 · Anticancer research
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    ABSTRACT: The present study has investigated the effect of panipenem, a widely used antibiotic, on the pharmacokinetics of an active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxy-camptothecin (SN-38) and SN-38 glucuronide (SN-38G) produced by uridine-diphosphate glucuronosyltransferase (UGT) 1A isoform-mediated glucuronidation in rats. Rats received a 1 h infusion with panipenem at a loading dose of 10 mg/kg and a maintenance dose of 15 mg/min/kg once a day for 5 days. When the effect of pretreatment with panipenem on glucuronidation activities of substrates for hepatic UGT1A isoforms was investigated using substrates 4-methylumbelliferone (4MU), estradiol and SN-38, the rate of 4MU glucuronide formation was significantly increased, but that of estradiol glucuronide formation was unchanged. However, the rate of SN-38G formation showed a tendency to increase. One hour after the final infusion of panipenem or saline, SN-38 (2 mg/kg) was administered intravenously in rats with or without bile duct cannulation. Pretreatment with panipenem had no effect on the plasma concentration-time curves and biliary excretion of SN-38 and SN-38G in rats with and without bile duct cannulation. There were also no significant differences in the relative extent of glucuronidation of SN-38 to SN-38G (AUC(2 h, SN-38G)/AUC(2 h, SN-38)) between panipenem-treated and untreated rats. These findings suggest that pretreatment with panipenem does not alter the pharmacokinetics of SN-38 and SN-38G, suggesting the possibility that panipenem can be used safely for cancer patients undergoing irinotecan chemotherapy.
    No preview · Article · Sep 2011 · Anticancer research