論文 - 秋好　健志

Decrease in ciprofloxacin absorption by polyvalent metal cations is not fully attributable to chelation or adsorption.

Imaoka A, Hattori M, Akiyoshi T, Ohtani H

Drug metabolism and pharmacokinetics （Drug Metabolism and Pharmacokinetics）  29 （ 5 ） 414 - 418 2014年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1347-4367

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Copyright © 2014 by the Japanese Society for the Study of Xenobiotics (JSSX). The drug interaction between new quinolone antibiotics (NQs) and polyvalent metal cation products, leading to a significant decrease in the absorption of NQ, is considered to be attributable to the formation of poorly absorbable chelate and physicochemical adsorption of NQs to cation products. To clarify the mechanisms of this drug interaction in detail, we investigated the effects of Al3+ or Mg2+ on the membrane permeation profile of ciprofloxacin (CPFX) across human colon carcinoma cell lines (Caco-2) in monolayer culture, and characterized the adsorption nature of CPFX to polyvalent metal cation products under physiological conditions. As a result, Al3+ or Mg2+ partially but not fully impaired the permeation of CPFX across Caco-2 monolayer up to 30% or 60% of control, respectively. Physicochemical adsorption of CPFX to cation products was not observed under physiological pH. In conclusion, two possible mechanisms investigated, the decrease in the permeability of CPFX by chelate formation and adsorption of CPFX to polyvalent metal cation products, may partially but not fully explain the extent of the drug interaction clinically observed.

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Prediction of the extent and variation of grapefruit juice-drug interactions from the pharmacokinetic profile in the absence of grapefruit juice.

Kogure N, Akiyoshi T, Imaoka A, Ohtani H

Biopharmaceutics & drug disposition （Biopharmaceutics and Drug Disposition）  35 （ 7 ） 373 - 381 2014年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0142-2782

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Copyright © 2014 John Wiley & Sons, Ltd. The aim of this study was to develop a method for predicting the extent of grapefruit juice (GFJ)-drug interactions and their interindividual variations from the pharmacokinetic profile in the absence of GFJ. The pharmacokinetic profiles of 13 drugs after intravenous and oral administration were used to develop and validate the method. For each drug, the proportion absorbed into the intestine and the intestinal availability (Fg) were calculated from clinical data taken from the literature. Then, the AUC ratio (the ratio of the AUC with GFJ to that without GFJ) was predicted by assuming that Fg was 1.0 when GFJ was concomitantly ingested. According to the developed method, the AUC ratio of felodipine was 2.50 and its coefficient of variation (CV) was 45%, which agreed well with the observed AUC ratio of 2.48 and CV of 51%. Although the developed method overestimated the AUC ratios of some drugs such as nisoldipine, no underestimation occurred. The predicted CV values were consistent with those observed. The developed method might be useful to predict the AUC ratio, along with its interindividual variation, from the pharmacokinetic profile in the absence of grapefruit juice.

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Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants.

Akiyoshi T, Ito M, Murase S, Miyazaki M, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H

Drug metabolism and pharmacokinetics （Drug Metabolism and Pharmacokinetics）  25 （ 5 ） 411 - 415 2013年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1347-4367

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Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a timedependent manner. The maximum inactivation rate constants, kinact,max, of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The KI values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI. © 2013 by the Japanese Society for the Study of Xenobiotics (JSSX).

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Effect of aromatase inhibitors on bone mineral density in a Japanese breast cancer population.

Akiyoshi T, Shimomura Y, Masuda S, Okamoto Y, Hiura S, Kato H, Asayama T, Ohtani H

Drug metabolism and pharmacokinetics （Drug Metabolism and Pharmacokinetics）  25 （ 5 ） 446 - 450 2013年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1347-4367

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We retrospectively analyzed the bone mineral density (BMD) of postmenopausal Japanese women taking an aromatase inhibitor (AI), exemestane, anastrozole or letrozole, and calculated the decrease rate constant of BMD in each individual to compare the influence of the three AIs on BMD. We also aimed to evaluate the preventive effect of bisphosphonates (BPs) on the AI-induced decrease in BMD. The decrease rate constant of BMD (ke) in each individual was determined as a slope of linear regression of the relationship between time and logarithm of BMD value in each patient during the AI therapy. To compensate for the age-related change in BMD level, we estimated the age-related decrease rate constant of BMD (ke,0) in healthy Japanese postmenopausal women from the literature. AIs decreased BMD with a ke value of -0.0329 yr-1, which was 4.7-fold larger than the ke,0 value of -0.00699 yr-1. No significant difference was detected in the influence on BMD among AIs. Co-administration of BP ameliorated the ke value to -0.0117 yr-1, a value similar to ke,0. The influence of AIs on BMD was quantitatively evaluated by using the decrease rate constant of BMD (ke). The present study also suggests that BPs may be useful to prevent the decrease in BMD induced by AIs. © 2013 by the Japanese Society for the Study of Xenobiotics (JSSX).

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Stability of the admixture of trace elements and vitamin-containing TPN solution in a multi-chamber bag (Fulcaliq).

Okuyama Y, Akiyoshi T, Asayama T, Hirai M, Matsuyama K Ohtani H* .

The Journal of Asian Association of Schools of Pharmacy 1 （ 3 ） 152 - 158 2012年09月

研究論文（学術雑誌）, 共著, 査読有り

Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.

Akiyoshi T, Saito T, Murase S, Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H

Drug metabolism and disposition: the biological fate of chemicals （Drug Metabolism and Disposition）  39 （ 4 ） 724 - 728 2011年04月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0090-9556

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CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the Ki value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the Ki value for CMD was 0.64-fold lower. In CYP3A4.16, the Ki value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the Ki value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the Ki values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

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未来先導型の研究と教育を目指して.

大谷壽一, 秋好健志.

薬剤学 （薬剤学）  70(4)   218-223 2010年07月

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Stability of gabexate mesilate products: Influence of the addition of mannitol.

Sakurai M, Abe H, Okamura N, Inoue Y, Akiyoshi T, Matsuyama K, Uchida T, Otsuka M

Bio-medical materials and engineering （Bio-Medical Materials and Engineering）  20 （ 1 ） 13 - 20 2010年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0959-2989

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Gabexate mesilate is a non-peptide protease inhibitor, developed in Japan, which is used in the treatment of acute pancreatitis and disseminated intravascular coagulation. This compound is readily hydrolyzed as it has ester bonds in its structure. It is now out of patent in Japan and there are many generic versions on the market. The crystal structure and the hydrolysate content of the branded product and nine generic versions were evaluated by X-ray diffractometry, thermal analysis and HPLC. The results showed that generic products containing mannitol as an additive had a higher content of hydrolysate as an impurity than the branded product or generic products formulated without mannitol, suggesting that the crystal structure might be altered and stability impaired in mannitol-containing drug products. © 2010 - IOS Press and the authors. All rights reserved.

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The potential of vitamin K3 as an anticancer agent against breast cancer that acts via the mitochondria-related apoptotic pathway.

Akiyoshi T, Matzno S, Sakai M, Okamura N, Matsuyama K

Cancer chemotherapy and pharmacology （Cancer Chemotherapy and Pharmacology）  65 （ 1 ） 143 - 150 2009年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0344-5704

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Purpose: We tried to clarify the cytotoxic mechanism of VK3 using the breast cancer cell line MCF-7. Methods: Cytotoxicity was measured via intracellular esterase activity. DNA fragmentation was assessed by agarose gel electrophoresis. JC-1 staining was applied to measure mitochondrial dysfunction. Caspase activation and reactive oxidative species (ROS) generation were also measured. Results: VK3 exhibited cytotoxicity that caused DNA fragmentation in MCF-7 cells with an IC50 of 14.2 μM. JC-1 staining revealed that VK3 caused mitochondrial dysfunction including a disappearance of mitochondrial membrane potential. Additional investigation showed that the mitochondrial damage was induced by the generation of ROS and the subsequent activation of caspase-7 and -9. Conclusions: Our findings demonstrate that VK3-induced apoptosis is selectively initiated by the mitochondria-related pathway and might be useful in breast cancer chemotherapy. © 2009 Springer-Verlag.

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Synergistic action of statins and nitrogen-containing bisphosphonates in the development of rhabdomyolysis in L6 rat skeletal myoblasts.

Nishiguchi T, Akiyoshi T, Anami S, Nakabayashi T, Matsuyama K, Matzno S

The Journal of pharmacy and pharmacology （Journal of Pharmacy and Pharmacology）  61 （ 6 ） 781 - 788 2009年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0022-3573

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Objectives: Nitrogen-containing bisphosphonates, which are widely used to treat osteoporosis, act as inhibitors of farnesyl pyrophosphate synthase, one of the key enzymes of the mevalonate pathway, and thus may have the potential to enhance the effect of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase). In this study, we evaluated the synergistic effect of two nitrogen-containing bisphosphonates, alendronate and risedronate, in statin-induced apoptosis in rat skeletal L6 myoblasts. Methods: L6 rat myoblasts were differentiated with drugs. DNA fragmentation was measured and small GTPase was detected by immunoblotting. Key findings: Alendronate and risedronate caused dose-dependent apoptosis of L6 myoblasts. Risedronate induced detachment of rho GTPase from the cell membrane, followed by activation of the caspase-8-related cascade. Risedronate-induced apoptosis was synergistically enhanced with atorvastatin and significantly reduced by addition of geranylgeraniol. By contrast, alendronate did not reduce membrane GTPases and the apoptosis was caspase independent. Conclusions: These results suggest that risedronate-induced apoptosis is related to geranylgeranyl pyrophosphate depletion followed by rho detachment, whereas alendronate affects are independent of rho. Our results suggest a risk of synergistic action between nitrogen-containing bisphosphonates and statins in the development of rhabdomyolysis when treating osteoporosis in women with hyperlipidaemia. © 2009 The Authors.

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An attempt to evaluate the effect of vitamin K3 using as an enhancer of anticancer agents.

Matzno S, Yamaguchi Y, Akiyoshi T, Nakabayashi T, Matsuyama K

Biological & pharmaceutical bulletin （Biological and Pharmaceutical Bulletin）  31 （ 6 ） 1270 - 1273 2008年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0918-6158

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The possibility of vitamin K3 (VK3) as an anticancer agent was assessed. VK3 dose-dependently diminished the cell viability (measured as esterase activity) with IC50 of 13.7 μM and Hill coefficient of 3.1 in Hep G2 cells. It also decreased the population of S phase and arrested cell cycle in the G2/M phase in a dose-dependent manner. G2/M arrest was regulated by the increment of cyclin A/cdk1 and cyclin A/cdk2 complex, and contrasting cyclin B/cdk1 complex decrease. Finally, combined application demonstrated that VK3 significantly enhanced the cytotoxicity of etoposide, a G2 phase-dependent anticancer agent, whereas it reduced the cytotoxic activity of irinotecan, a S phase-dependent agent. These findings suggest that VK3 induces G 2/M arrest by inhibition of cyclin B/cdk1 complex formation, and is thus useful as an enhancer of G2 phase-dependent drugs in hepatic cancer chemotherapy. © 2008 Pharmaceutical Society of Japan.

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Effects of quinine on the intracellular calcium level and membrane potential of PC 12 cultures.

Akiyoshi T, Tanaka N, Nakamura T, Matzno S, Shinozuka K, Uchida T

The Journal of pharmacy and pharmacology （Journal of Pharmacy and Pharmacology）  59 （ 11 ） 1521 - 1526 2007年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0022-3573

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The mechanism for the perception of bitterness appears to be quite complicated, even for quinine, which is a model bitter substance, and thus has yet to be completely elucidated. To investigate the possibility of being able to predict the bitterness of quinine solutions, we examined the effects of quinine on intracellular calcium ion concentration ([Ca2+]i) and membrane potentials in PC 12 cultures. [Ca2+]i and membrane potentials were analysed by fluorescence confocal microscopic imaging using the Ca 2+-sensitive probe Calcium Green 1/AM and the membrane potential-sensitive probe bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4(3)). Quinine elicited an increase in the membrane potential along with a concentration-dependent increase in [Ca2+]i. These increases were inhibited by extracellular Ca2+-free conditions, thapsigargin, which is a Ca2+-pump inhibitor, and U73122, which is a phospholipase C inhibitor. The quinine-induced increase in [Ca2+]i levels was inhibited by nifedipine, an L-type Ca2+-channel blocker, ufconotoxin, a T-type Ca2+-channel blocker, and BMI-40, which is a bitterness-masking substance. These results suggest that responses in PC 12 cultures may be used as a simple model of bitterness perception. © 2007 The Authors.

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Clofibrate-induced apoptosis is mediated by Ca2+-dependent caspase-12 activation.

Matzno S, Yasuda S, Kitada Y, Akiyoshi T, Tanaka N, Juman S, Shinozuka K, Nakabayashi T, Matsuyama K

Life sciences （Life Sciences）  78 （ 16 ） 1892 - 1899 2006年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0024-3205

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The mechanism of fibrate-induced myopathy was investigated in this report. When clofibrate (30 to 300 μM) was applied to L6 rat skeletal myoblasts, dose-dependently apoptosis was observed within 24 h. In the apoptotic myoblasts, a caspase-12 cleavage was observed at 2 h and with following caspases-9 and -3-related cascade activation. In contrast, the neutral protease calpain, that is a key enzyme in ER stress-related apoptosis via caspase-12 activation, was significantly decreased during apoptosis. Next, the authors evaluated a role of calcium-dependent signal(s). When clofibrate was added into medium, cytosolic calcium concentration was rapidly and persistently increased. On the other hand, an addition of 10 mM EGTA depressed sustained calcium phase, and concurrent myoblasts apoptosis was completely inhibited. Taken together, our findings indicate that the clofibrate-induced myopathy is triggered by Ca2+ influx, then activated cytosolic caspase-12 through calpain-independent cascade, and consequently caused apoptotic DNA fragmentation. © 2005 Elsevier Inc. All rights reserved.

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高速液体クロマトグラフィによる血清中アミオダロン濃度測定時における採血管分離ゲル剤からの溶出物質による妨害ピークの影響.

上野和行,秋好健志, 川井仁之, 今野秀樹, 桑原史郎, 米田孝司, 片山善章.

TDM研究 20(3)   274-9 2003年07月

研究論文（学術雑誌）, 共著, 査読有り

Effect of quinine solutions on intracellular Ca2+ levels in neuro-2a cells--conventional physiological method for the evaluation of bitterness.

Nakamura T, Akiyoshi T, Tanaka N, Shinozuka K, Matzno S, Nakabayashi T, Matsuyama K, Kashiwayanagi M, Uchida T

Biological & pharmaceutical bulletin （Biological and Pharmaceutical Bulletin）  26 （ 11 ） 1637 - 40 2003年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0918-6158

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The purpose of the present study was to examine the effect of quinine on intracellular Ca2+ ([Ca2+]i) levels in cultured neuro-2a cells, and to investigate the possibility of using [Ca 2+]i levels to predict the bitterness of quinine solutions. [Ca2+]i levels in neuro-2a cells increased following stimulation by quinine in a concentration-related manner. There was a good linear correlationship between the quinine-induced increase in [Ca 2+]i levels increase and the bitterness scores of the quinine solutions as assessed in human gustatory sensation tests (r 2=0.918). The quinine-induced increase in [Ca2+] i levels was inhibited by thapsigargin (an inhibitor of the Ca 2+ pump into intracellular stores), U73122 (an inhibitor of phospholipase C) and ω-conotoxin (an N-type Ca2+-channel blocker), but not by nifedipine (an L-type Ca2+-channel blocker). © 2003 Pharmaceutical Society of Japan.

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The effect of various substances on the suppression of the bitterness of quinine-human gustatory sensation, binding, and taste sensor studies.

Nakamura T, Tanigake A, Miyanaga Y, Ogawa T, Akiyoshi T, Matsuyama K, Uchida T.

Chemical & pharmaceutical bulletin 50 （ 12 ） 1589 - 1593 2002年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0009-2363

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