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Effects of duration of phenytoin administration on mRNA expression of cytochrome P450 and P-glycoprotein in the liver and small intestine of rats

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Asian Journal of Pharmaceutical Sciences 2016年第5期11卷 662-667页

作者： Atsushi Kawase Hiroyuki Tanaka Toru Otori Kenji Matsuyama masahiro iwaki Department of Pharmacy Faculty of PharmacyKindai University

Phenytoin(5,5-diphenylhydantoin;DPH) induces expression of cytochromes P450(CYPs). Interactions between DPH and tacrolimus suggested that the persistence of CYP induction after discontinuation of DPH is dependent on the history of administration and dosing period of DPH. However, the relationship between the duration of DPH administration and expression of CYPs in the liver and small intestine of rats is not known. Alterations in levels of P-glycoprotein(P-gp;MDR1;ABCB1) as well as CYPs cause drug interactions in the small intestine. We examined the effects of the duration of DPH administration on expression of CYPs and P-gp in the liver and small intestine of rats. Rats were treated with DPH(100 mg/kg,peroral(p.o.) twice a day(b.d.)) for 2, 4, 8, and 16 d. mRNA levels of CYPs and P-gp were examined using the total RNA extracted from the liver and duodenum 2 h and 24 h after the final administration of DPH. CYP3 A activities were determined using microsomes. DPH administration for 2 d and 4 d markedly increased m RNA levels of CYPs such as CYP3 A1, CYP3 A2,CYP2 B1, and CYP2 B2 in the liver. A relatively long duration of DPH administration(8 d and16 d) resulted in abolition of the induction of hepatic CYP but increased CYP3 A activities were maintained. These results suggest that the duration of DPH administration could be an important determinant of hepatic CYP induction.

关键词： Phenytoin Cytochromes P450 Microsomes mRNA Liver

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Changes in mRNA Expression and Activity of Xenobiotic Metabolizing Enzymes in Livers from Adjuvant-Induced Arthritis Rats

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Pharmacology & Pharmacy 2013年第6期4卷 478-483页

作者： Atsushi Kawase Syoko Wada masahiro iwaki Department of Pharmacy School of Pharmacy Kinki University Osaka Japan Department of Pharmacy School of Pharmacy Kinki University Osaka Japan.

Pathophysiological changes in human patients and in animal models of infection or inflammation are associated with alterations in the production of numerous liver-derived proteins including metabolizing enzymes. In this study, the effects of adjuvant-induced arthritis (AA) in rats on the levels of mRNA and activity of hepatic xenobiotic metabolizing enzymes were determined during the inflammatory response. The mRNA levels of cytochrome P450 (CYP) 1A2, CYP2C12, CYP2D1, CYP2D2, and CYP3A1 were significantly decreased compared with control levels in almost all phases of inflammation. A reduction in the activity of CYP2C and CYP3A, which are abundantly expressed in the liver, was also observed. For phase II metabolizing enzymes, mRNA levels of uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A1, UGT1A6, sulfotransferase (SULT) 2A1, and glutathione S-transferase 2 were significantly decreased compared with control levels. However, the mRNA levels of UGT2B and SULT1A1 returned to control levels during the subacute (7 d after adjuvant treatment) and chronic (21 d after adjuvant treatment) phases although these levels decreased during the acute (3 d after adjuvant treatment) phase. These results suggest that the effects of inflammation on the expression of xenobiotic metabolizing enzymes differ depending on the isoform of the enzyme and could affect the pharmacokinetics of each substrate.

关键词： Inflammation Arthritis Enzyme Cytochrome Metabolism

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布洛芬葡萄糖醛酸结合物的立体选择性胆排泄及其机制研究(英文)

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中国临床药理学与治疗学 2007年第10期12卷 1163-1167页

作者： CHEN Xi-jing masahiro iwaki Center of Drug Metabolism ＆ Pharmacokinetics China Pharmaceutical University Nanjing 210009 Jiangsu China School of pharmaceutical Science Kinki University Higashi-Osaka Osaka 577-8502 Japan

目的:为阐明药物转运体在布洛芬(IB)葡萄糖醛酸结合物(IBG)胆排泄中的作用,对IB和IBG在先天性高胆红素血症大鼠(EHBR)和正常SD大鼠(SDR)的胆排泄和血药浓度差异进行了研究。方法:按20 mg/kg剂量静脉注射IB消旋体后,以HPLC法测定了血和... 详细信息

目的:为阐明药物转运体在布洛芬(IB)葡萄糖醛酸结合物(IBG)胆排泄中的作用,对IB和IBG在先天性高胆红素血症大鼠(EHBR)和正常SD大鼠(SDR)的胆排泄和血药浓度差异进行了研究。方法:按20 mg/kg剂量静脉注射IB消旋体后,以HPLC法测定了血和胆汁中IB与IBG的浓度。结果:结果表明IBG的胆排泄在EHBR受到了明显抑制,其S-型和R-型IBG的6小时胆排泄量分别为给药量的1.7 %±1.0 %和0.6 %±0.9 %,而在SDR,该值分别为18.4 %±4.0 %和3.0 %±2.4 %。这些结果同时显示了S-型IBG在两种大鼠的胆排泄量均较R-型IBG大,说明该过程存在明显的立体选择性。由于IBG在EHBR的胆排泄受到抑制,其血中的浓度较高。结论:EHBR是一种先天性多药耐药相关蛋白(Mrp2)缺失的大鼠,可以推测布洛芬葡萄糖醛酸结合物的胆排泄过程主要是由Mrp2介导。但由于IBG在EHBR仍有少量胆排泄,故不排除其它转运体参与该过程的可能性。

关键词：布洛芬葡萄糖醛酸结合物 EHBR Mrp2 胆排泄立体选择性

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Diurnal Variation of Nuclear Receptors in Mice with or without Fasting

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Pharmacology & Pharmacy 2013年第2期4卷 240-243页

作者： Atsushi Kawase Tetsuya Ohgami Iho Yoshida Yu Tsunokuni masahiro iwaki Department of Pharmacy School of Pharmacy Kinki University Osaka Japan Department of Physiology Hyogo College of Medicine Nishinomiya Japan.

Nuclear receptors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate the transcription of transporter and cytochrome P450 (CYP). The diurnal variation was observed in some transporters regulated by nuclear receptors. We investigated whether diurnal variation in PXR and CAR exists in mice. We also examined the effect of food intake on the diurnal rhythm of hepatic PXR and CAR using fed and fasted mice. In liver and small intestine of fed mice, the mRNA levels of PXR and CAR were unchanged between 7:00 AM and 7:00 PM. In contrast to fed mice, fasting mice partly exhibited the diurnal variation in PXR, not in CAR. The mRNA levels of PXR at 7:00 AM were significantly higher than that those at 7:00 PM in liver of fasting mice. These results indicated the different effects of fasting in mice on diurnal variation of PXR in each tissue.

关键词： CAR Circadian Rhythm Diurnal Variation Fasting Nuclear Receptor PXR

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布洛芬葡萄糖醛酸结合物的立体选择性胆排泄及其机制研究(英文)

布洛芬葡萄糖醛酸结合物的立体选择性胆排泄及其机制研究(英文)

引用

中国药理学会临床药理学专业委员会会议暨第十次全国临床药理学学术会议

作者： masahiro iwaki School of pharmaceutical Science Kinki University Higashi-OsakaOsaka 577-8502Japan

目的：为阐明药物转运体在布洛芬(IB)葡萄糖醛酸结合物(IBG)胆排泄中的作用,对 IB 和 IBG 在先天性高胆红素血症大鼠(EHBR)和正常 SD 大鼠 (SDR)的胆排泄和血药浓度差异进行了研究。方法：按20 mg/kg 剂量静脉注射 IB 消旋体后,以 HPLC... 详细信息

目的：为阐明药物转运体在布洛芬(IB)葡萄糖醛酸结合物(IBG)胆排泄中的作用,对 IB 和 IBG 在先天性高胆红素血症大鼠(EHBR)和正常 SD 大鼠 (SDR)的胆排泄和血药浓度差异进行了研究。方法：按20 mg/kg 剂量静脉注射 IB 消旋体后,以 HPLC 法测定了血和胆汁中 IB 与 IBG 的浓度。结果：结果表明 IBG 的胆排泄在 EHBR 受到了明显抑制,其 S- 型和 R-型 IBG 的6小时胆排泄量分别为给药量的 1．7％±1．0％和0．6％±0．9％,而在 SDR,该值分别为18．4％±4．0％和3．0％±2．4％。这些结果同时显示了 S-型 IBG 在两种大鼠的胆排泄量均较 R- 型 IBG 大,说明该过程存在明显的立体选择性。由于 IBG 在 EHBR 的胆排泄受到抑制,其血中的浓度较高。结论：EHBR 是一种先天性多药耐药相关蛋白(Mrp2)缺失的大鼠,可以推测布洛芬葡萄糖醛酸结合物的胆排泄过程主要是由 Mrp2介导。但由于 IBG 在 EHBR 仍有少量胆排泄,故不排除其它转运体参与该过程的可能性。

关键词：布洛芬葡萄糖醛酸结合物 EHBR Mrp2 胆排泄立体选择性

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Clinicopathological Analysis of Patients with Nonmuscle-Invasive Bladder Cancer Who Underwent Radical Cystectomy

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Surgical Science 2012年第7期3卷 347-352页

作者： Naotaka Nishiyama Hiroshi Kitamura Masatoshi Mutoh masahiro Yanase Hiroyuki iwaki Tadashi Hasegawa Taiji Tsukamoto Departments of Surgical Pathology Sapporo Medical University School of Medicine Sapporo Japan Departments of Urology Sapporo Medical University School of Medicine Sapporo Japan Divisions of Pathology Sunagawa City Medical Center Sunagawa Japan Divisions of Urology Sunagawa City Medical Center Sunagawa Japan

Objectives: Surgical specimens obtained at the time of the last transurethral resection of bladder tumor (TURBT) for patients with nonmuscle-invasive bladder cancer (NMIBC) who underwent radical cystectomy were retrospectively evaluated in order to investigate the relationship between pathological variation and upstaging of NMIBC. Methods and Materials: Twenty patients (19 men, 1 woman;aged 69.4 ± 12.1 (mean ± SD) years) diagnosed with NMIBC underwent radical cystectomy during follow-up. Results: Five of the 20 patients (25%) had pathological upstaging in the radical cystectomy specimens. There was a statistical association between pathological upstaging and cancer death (p = 0.002). There were three patterns of pathological variation in the upstaged specimens: 1) in patients with BCG-resistant NMIBC, urothelial carcinoma invaded through the lamina propria;2) urothelial carcinoma showed diffuse invasion beyond the deep lamina propria, and the cancer cells had infiltrated as single cells and formed nodules;3) TURBT specimens showed a micropapillary variant. Conclusions: Since these pathological variations correlated with pathological upstaging, they may provide an indication for cystectomy in NMIBC patients.

关键词： Clinicopathological Examination Nonmuscle-Invasive Bladder Cancer Radical Cystectomy Pathological Upstaging

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