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| 1.
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Hosomi, Atsushi ; Nakanishi, Takeo ; Fujita, Takuya ; Tamai, Ikumi
概要:
Urinary excretion accounts for two-thirds of total elimination of uric acid and the remainder is excreted in feces. Howe
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ver, the mechanism of extra-renal elimination is poorly understood. In the present study, we aimed to clarify the mechanism and the extent of elimination of uric acid through liver and intestine using oxonate-treated rats and Caco-2 cells as a model of human intestinal epithelium. In oxonate-treated rats, significant amounts of externally administered and endogenous uric acid were recovered in the intestinal lumen, while biliary excretion was minimal. Accordingly, direct intestinal secretion was thought to be a substantial contributor to extra-renal elimination of uric acid. Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and genetic polymorphism causing a decrease of BCRP activity is known to be associated with hyperuricemia and gout, the contribution of rBcrp to intestinal secretion was examined. rBcrp was confirmed to transport uric acid in a membrane vesicle study, and intestinal regional differences of expression of rBcrp mRNA were well correlated with uric acid secretory activity into the intestinal lumen. Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor, elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of elacridar. These results demonstrate that BCRP contributes at least in part to the intestinal excretion of uric acid as extra-renal elimination pathway in humans and rats. © 2012 Hosomi et al.
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| 2.
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Tamai, Ikumi
概要:
The carnitine/organic cation transporter (OCTN) family consists of three transporter isoforms, i.e. OCTN1 (SLC22A4) and
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OCTN2 (SLC22A5) in humans and animals and Octn3 (Slc22a21) in mice. These transporters are physiologically essential to maintain appropriate systemic and tissue concentrations of carnitine by regulating its membrane transport during intestinal absorption, tissue distribution and renal reabsorption. Among them, OCTN2 is a sodium-dependent, high-affinity transporter of carnitine, and a functional defect of OCTN2 due to genetic mutation causes primary systemic carnitine deficiency (SCD). Since carnitine is essential for beta-oxidation of long-chain fatty acids to produce ATP, OCTN2 gene mutation causes a range of symptoms, including cardiomyopathy, skeletal muscle weakness, fatty liver and male infertility. These functional consequences of Octn2 gene mutation can be seen clearly in an animal model, jvs mouse, which exhibits the SCD phenotype. In addition, although the mechanism is not clear, single nucleotide polymorphisms of OCTN1 and OCTN2 genes are associated with increased incidences of rheumatoid arthritis, Crohn's disease and asthma. OCTN1 and OCTN2 accept cationic drugs as substrates and contribute to intestinal and pulmonary absorption, tissue distribution (including to tumour cells), and renal excretion of these drugs. Modulation of the transport activity of OCTN2 by externally administered drugs may cause drug-induced secondary carnitine deficiency. Octn3 transports carnitine specifically, particularly in male reproductive tissues. Thus, the OCTNs are physiologically, pathologically and pharmacologically important. Detailed characterization of these transporters will greatly improve our understanding of the pathology associated with common diseases caused by functional deficiency of OCTNs. © 2012 John Wiley & Sons, Ltd.
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| 3.
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Arakawa, Hiroshi ; Shirasaka, Yoshiyuki ; Haga, Makoto ; Nakanishi, Takeo ; Tamai, Ikumi
概要:
Fluoroquinolone antimicrobial drugs are absorbed efficiently after oral administration despite of their hydrophilic natu
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re, implying an involvement of carrier-mediated transport in their membrane transport process. It has been that several fluoroquinolones are substrates of organic anion transporter polypeptides OATP1A2 expressed in human intestine derived Caco-2 cells. In the present study, to clarify the involvement of OATP in intestinal absorption of ciprofloxacin, the contribution of Oatp1a5, which is expressed at the apical membranes of rat enterocytes, to intestinal absorption of ciprofloxacin was investigated in rats. The intestinal membrane permeability of ciprofloxacin was measured by in situ and the vascular perfused closed loop methods. The disappeared and absorbed amount of ciprofloxacin from the intestinal lumen were increased markedly in the presence of 7,8-benzoflavone, a breast cancer resistance protein inhibitor, and ivermectin, a P-glycoprotein inhibitor, while it was decreased significantly in the presence of these inhibitors in combination with naringin, an Oatp1a5 inhibitor. Furthermore, the Oatp1a5-mediated uptake of ciprofloxacin was saturable with a K mvalue of 140 μm, and naringin inhibited the uptake with an IC 50value of 18 μm by Xenopus oocytes expressing Oatp1a5. Naringin reduced the permeation of ciprofloxacin from the mucosal-to-serosal side, with an IC 50 value of 7.5 μm by the Ussing-type chamber method. The estimated IC 50 values were comparable to that of Oatp1a5. These data suggest that Oatp1a5 is partially responsible for the intestinal absorption of ciprofloxacin. In conclusion, the intestinal absorption of ciprofloxacin could be affected by influx transporters such as Oatp1a5 as well as the efflux transporters such as P-gp and Bcrp. Copyright © 2012 John Wiley & Sons, Ltd.
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| 4.
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Arakawa, Hiroshi ; Nakanishi, Takeo ; Yanagihara, Chihiro ; Nishimoto, Tomohiro ; Wakayama, Tomohiko ; Mizokami, Atsushi ; Kawai, Keiichi ; Tamai, Ikumi
概要:
The biological mechanisms underlying castration resistance of prostate cancer are not fully understood. In the present s
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tudy, we examined the role of organic anion transporting polypeptides (OATPs) as importers of dehydroepiandrosterone sulfate (DHEAS) into cells to support growth under androgen-depleted conditions. Cell growth and mRNA expression of OATP genes were studied in human prostate cancer LNCaP and 22Rv1 cells under androgen-depleted conditions. The stimulatory effect of DHEAS on cell growth was investigated in LNCaP cells in which OATP1A2 had been silenced. Growth of both cell lines was stimulated by DHEAS and the effect was attenuated by STX64, an inhibitor of steroid sulfatase which can covert DHEAS to DHEA. OATP1A2 mRNA expression was increased most prominently among various genes tested in LNCaP cells grown in androgen-depleted medium. Similar results were obtained with 22Rv1 cells. Furthermore, the characteristics of [ 3H]DHEAS uptake by LNCaP cells were consistent with those of OATP-mediated transport. Knockdown of OATP1A2 in LNCaP cells resulted in loss of the DHEAS sensitivity of cell growth. Our results suggest that enhanced OATP1A2 expression is associated with adaptive cell growth of prostate cancer cells under androgen-depleted conditions. Thus, OATP1A2 may be a pharmacological target for prostate cancer treatment. © 2012 Elsevier Inc.
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| 5.
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Nakamura, Toshimichi ; Yoshida, Kenji ; Yabuuchi, Hikaru ; Maeda, Tomoji ; Tamai, Ikumi
概要:
金沢大学医薬保健研究域薬学系<br />It has been reported that organic cation/carnitine transporter 1 (OCTN1) is associated with rheumato
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id arthritis and Crohn's disease. Additionally, we reported that OCTN1 is expressed in hematopoietic cells, and is associated with proliferation and differentiation of erythroid cells. However, physiological role of OCTN1 is still unclear. Ergothioneine, an anti-oxidant, was recently reported to be a good substrate of human OCTN1. However, the transport characteristics of ergothioneine in rat remains to be clarified. The present study, is to further investigate the role of rat Octn1 on transport of ergothioneine in rat Octn1 transfected cells and natively expressing cell line PC12 derived from rat adrenal pheochromocytoma. [3H]Ergothioneine uptake by rat Octn1 stably transfected HEK293 cells was saturable, sodium dependent with 1:1 stoichiometry of ergothioneine, and pH dependent. Since ergothioneine was reported to presumably play a protective role against oxidative stress-induced apoptosis in PC12 cells, its transport in this cell line was investigated. The expression of rat Octn1 and a saturable and Na +-dependent transport of ergothioneine were observed in PC12 cells, suggesting that ergothioneine transport in this cell line may be mediated by rat Octn1. These findings suggested that rat Octn1 may act as a survival factor by taking up ergothioneine to suppress oxidative stress in this cell line. In conclusion, functional characteristics of ergothioneine transport by rat Octn1 is similar to that of human OCTN1 and it is suggested that rat Octn1 is important by transporting anti-oxidant ergothioneine in PC12 cells, though its role in vivo is to be investigated. © 2008 Pharmaceutical Society of Japan.
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| 6.
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Saheki, Akira ; Fukui, Yoshiharu ; Hoshi, Yuji ; Fukui, Hiroshi ; Seki, Junzo ; Tamai, Ikumi
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金沢大学医薬保健研究域薬学系<br />Conformations of polyinosinic acid [poly(I)] and polycytidylic acid [poly(C)] in liposomes (lipoplex
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) were investigated by both circular dichroism (CD) spectroscopy and fluorescence resonance energy transfer (FRET) measurements, and compared with those in aqueous solution. The results indicate that poly(I) and poly(C) take double-stranded structure in aqueous solution at pH 6.5-7.5 in the presence of NaCl at higher concentration than 50 mM. Although lipoplex was prepared without NaCl to avoid aggregation of lipoplex particles, poly(I) and poly(C) were double-stranded in pre-mixed poly(I)/poly(C) lipoplex (pre-mixed LIC), prepared by adding a mixed solution of poly(I) and poly(C) to the cationic liposomes. However, poly(I) and poly(C) did not take double-stranded structure in separately mixed LIC, prepared by separate addition of poly(I) solution and poly(C) solution to the cationic liposomes. The physicochemical properties (particle diameter and zeta potential) of pre-mixed LIC and separately mixed LIC were not different, but the anti-proliferative effect of pre-mixed LIC on human epidermoid carcinoma A431 cells was about eight times greater than that of separately mixed LIC. Our results indicate that polynucleotide conformation in lipoplex is markedly influenced by the preparation method, and the polynucleotide conformation in lipoplex has a substantial effect on pharmacological activity. © 2010 Elsevier B.V. All rights reserved.
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| 7.
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Mitsuoka, Keisuke ; Tamai, Ikumi ; Morohashi, Yasushi ; Kubo, Yoshiyuki ; Saitoh, Ryoichi ; Tsuji, Akira ; Kato, Yukio
概要:
The oligopeptide transporter PEPT1 (SLC15A1) is responsible for absorption of peptidic nutrients in the small intestine.
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Although the L-diastereomer of the β-lactam antibiotic cephalexin (L-cephalexin) is likely to be transported by PEPT1, there has been no direct demonstration of PEPT1-mediated L-cephalexin transport. Indeed, after the incubation with L-cephalexin, the intact form of L-cephalexin has not been identified inside vesicles/proteoliposomes prepared from brush border membrane of intestinal epithelial cells or cultured cell lines exogenously transfected with PEPT1 gene. Thus, it appears that L-cephalexin is rapidly metabolized by PEPT1 or PEPT1-associated proteins. Here, we attempted to verify whether L-cephalexin is transported by PEPT1 and whether it is hydrolyzed by PEPT1 itself, by using budded baculovirus expressing PEPT1 protein. Marked uptake of L-cephalexin in PEPT1-expressing budded baculovirus, compared with wild-type virus, indicated that L-cephalexin is a substrate for PEPT1. The uptake was found to be pH sensitive, and was strongly inhibited by the D-diastereomer of cephalexin and glycylsarcosine, but not by glycine. Thus, L-cephalexin is transported by PEPT1 itself. Upon the transport of both L- and D-cephalexin by PEPT1, dose-dependent membrane depolarization was observed; the EC50 values of 0.18 and 2.9 mM, respectively, indicate that the affinity of L-cephalexin for PEPT1-mediated transport is much higher than that of the D-diastereomer. On the other hand, the L-cephalexin metabolite 7-aminodesacetoxycephalosporanic acid was not detected in PEPT1-expressing or wild-type virus at either pH 6.0 or 7.4. We conclude that L-cephalexin is transported by PEPT1 with high affinity, but is not metabolized by PEPT1 itself. © 2009 Pharmaceutical Society of Japan.
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| 8.
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Tamai, Ikumi
概要:
Transporters play important roles in tissue distribution and urinary- and biliary-excretion of drugs and transporter mol
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ecules involved in those processes have been elucidated well. Furthermore, an involvement of efflux transporters such as P-glycoproteins, multidrug resistance associated protein 2, and breast cancer resistance protein as the intestinal absorption barrier and/or intestinal luminal secretion mechanisms has been demonstrated. However, although there are many suggestions for the contribution of uptake/influx transporters in intestinal absorption of drugs, information on the transporter molecules responsible for the intestinal absorptive process is limited. Among them, most studied absorptive drug transporter is peptide transporter PEPT1. However, utilization of PEPT1 for oral delivery of drugs may not be high due to the chemical structural requirement of PEPT1 limited to peptide-mimetics. Recently, organic anion transporting polypeptide (OATP) family such as OATP1A2 and OATP2B1 has been suggested to mediate intestinal absorption of several drugs. Since OATPs exhibit species difference in expressed tissues and functional properties between human and animals, human studies are essential to clarify the intestinal absorption mechanisms of drugs via OATPs. Recent pharmacogenomic studies demonstrated that OATP2B1 is involved in the drug absorption in human. In addition, information of drug-juice interaction in the intestine also uncovered the contribution of OATP1A2 and OATP2B1 in drug absorption. Since OATP1A2 and OATP2B1 exhibit broader substrate selectivity compared with PEPT1, their potential to be applied for oral delivery should be high. In this review, current understanding of characteristics and contribution as the absorptive transporters of OATPs in small intestine in human is described. Now, it is getting clearer that OATPs have significant roles in intestinal absorption of drugs, therefore, there are higher possibility to utilize OATPs as the tools for oral delivery. © 2011 Elsevier B.V. All rights reserved.
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| 9.
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Yashio, Keiji ; Katayama, Yumiko ; Takashima, Tadayuki ; Ishiguro, Naoki ; Doi, Hisashi ; Suzuki, Masaaki ; Wada, Yasuhiro ; Tamai, Ikumi ; Watanabe, Yasuyoshi
概要:
The synthesis and in vivo evaluation of 11C -labeled uric acid ([11C]1), a potential imaging agent for the diagnosis of
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urate-related life-style diseases, was performed using positron emission tomography (PET) image analysis. First, the synthesis of [11C]1 was achieved by reacting 5,6-diaminouracil (2) with 11C-labeled phosgene ([11C]COCl2). The radiochemical yield of [11C]1 was 37 ± 7% (decay-corrected based on [11C]COCl2) with specific radioactivities of 96-152 GBq/μmol at the end of synthesis (n = 6). The average time of radiosynthesis from the end of bombardment, including formulation, was about 30 min with >98% radiochemical purity. Second, the synthetic approach to [11C]1 was optimized using 5,6-diaminouracil sulfate (3) with [11C]COCl2 in the presence of 1,8-bis(dimethylamino)naphthalene. [11C]1 was synthesized in 36 ± 6% radiochemical yield, 89-142 GBq/μmol of specific radioactivities, and 98% radiochemical purity by this method (n = 5). This allowed the synthesis of [11C]1 to be carried out repeatedly and the radiochemical yield, specific radioactivities, average time of synthesis, and radiochemical purity of [11C]1 were similar to those obtained using 2. PET studies in rats showed large differences in the accumulation of radioligand in the limbs under normal and hyperuricemic conditions. Thus, an efficient and convenient automated synthesis of [11C]1 has been developed, and preliminary PET evaluation of [11C]1 confirmed the increased accumulation of radioactivity in the limbs of a rat model of hyperuricemia. © 2011 Elsevier Ltd. All rights reserved.
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| 10.
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玉井, 郁巳 ; Tamai, Ikumi
概要:
金沢大学医薬保健研究域薬学系 / 東京理科大学<br />医薬品の薬効・毒性への影響が大きい肝動態を決める、肝有機アニオン輸送体の種差に関する研究を行なった。特にOATP と呼ばれるは輸送体はヒト動物とも肝臓に複数のサブタイプが発現しており
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、種間の対応付けが不明であった。そこで、ヒトOATP とラットOatp 発現系、さらに両種からの肝細胞、ラット全身動態試験を行ない、機能的に対応する分子の同定を試みた。その結果、β-ラクタム抗生物質については、ヒトOATP1B3 とラットoatp1a4 が両種間機能的に対応する分子であることが示された。両者は遺伝子・アミノ酸配列として相同性が高くないため、動物の薬物動態データからヒト予測を行なうためには、タンパク質構造のみならず機能解析も行なう必要性を示し、今後の医薬品の開発・臨床適用における有用な知見を得ることが出来た。<br />研究課題/領域番号:19390046, 研究期間(年度):2007 – 2008<br />出典：「有機アニオン輸送体を介した薬物の肝移行性調節とその種差」研究成果報告書 課題番号19390046（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-19390046/19390046seika/)を加工して作成
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