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Akira Tsuji - One of the best experts on this subject based on the ideXlab platform.
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tissue selective drug delivery utilizing carrier Mediated Transport systems
Journal of Controlled Release, 1999Co-Authors: Akira TsujiAbstract:This paper describes some successful examples of a tissue selective drug delivery by utilizing specialized Transporter(s) expressed in the targeted tissue cells. These are as follows: (1) oral delivery via H + /oligopeptide Transporter, rat or human Peptl, in the intestine for β-lactam antibiotics and a newly synthesized dipeptide, L-dopa-L-phenylalanine; (2) tumor cell specific delivery via the newly discovered H + /oligopeptide Transporter(s) expressed in human fibrosarcoma cell line HT-1080 for model oligopeptides, glycylsarcosine and carnosine; (3) oral and hepatic delivery via an H + /monocarboxylate Transporter in the intestine and an organic anion Transporter in the liver for HMG-CoA reductase inhibitor, pravastatin; and (4) lung selective delivery via some type of Transporter and avoidance of transfer into the brain via P-glycoprotein at the blood-brain barrier for a new quinolone antibacterial, HSR-903.
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carrier Mediated Transport of oligopeptides in the human fibrosarcoma cell line ht1080
Cancer Research, 1997Co-Authors: Takeo Nakanishi, Takuma Sasaki, Ikumi Tamai, Akira TsujiAbstract:To explore the feasibility of targeting human tumor cells via their Transport systems, dipeptide uptake was studied in the human fibrosarcoma cell line HT1080 and the human fibroblast cell line IMR-90 by the use of hydrolysis-resistant glycylsarcosine (Gly-Sar). The uptake of [14C]Gly-Sar into HT1080 was time dependent. Kinetic analysis of the concentration dependence of the initial rate of [14C]Gly-Sar uptake showed that a carrier-Mediated Transport system with a K m of 11.4 ± 3.3 mm and V max of 26.8 ± 4.0 (nmol/15 min/mg protein) and a nonsaturable component ( k d of 0.80 µl/15 min/mg protein) were responsible for the dipeptide uptake by HT1080 cells. The optimal pH for the maximal uptake was around 6.0. [14C]Gly-Sar uptake was inhibited by various di- and tripeptides and peptide-mimetic drugs, such as bestatin and cefadroxil. [14C]Gly-Sar uptake was not affected by the presence of amino acids or tetra- or pentapeptides. The uptake of cefadroxil was reduced significantly by unlabeled Gly-Sar. Moreover, Gly-Gly and Gly-Leu produced an increase in the apparent K m of the uptake of Gly-Sar without altering V max. On the other hand, dipeptide uptake by IMR-90, which is a normal diploid cell line (not malignant), showed no saturable Transport. These results suggest that HT1080 cells take up dipeptides via a pH-dependent Transporter. This is the first report showing that a dipeptide Transport system, which is similar but not identical to the well-characterized oligopeptide Transporters PepT1 and PepT2, exists in fibroblast-derived tumor cells but not in normal fibroblasts. The present finding could be the basis of a novel strategy for the specific delivery of oligopeptide-mimetic anticancer drugs into tumor cells.
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transcellular Transport of benzoic acid across caco 2 cells by a ph dependent and carrier Mediated Transport mechanism
Pharmaceutical Research, 1994Co-Authors: Akira Tsuji, Hitomi Takanaga, Ikumi Tamai, Tetsuya TerasakiAbstract:The pH-dependent transcellular Transport of [14 C]benzoic acid across a Caco-2 cell monolayer is shown to be Mediated by a monocarboxylic acid-specific carrier-Mediated Transport system, localized on the apical membrane. Evidence for the carrier-Mediated Transport of benzoic acid includes (a) the significant temperature and concentration dependence, (b) the metabolic energy dependence, (c) the inhibition by unlabeled benzoic acid and other monocarboxylic acids, (d) counterTransport effects on the uptake of [14C]benzoic acid, and (e) effects of a proteinase (papain) and amino acid-modifying reagents. Furthermore, since carbonylcyanide p-trifluoromethoxyphenylhydrazone and nigericin significantly inhibited the Transport of [14C] benzoic acid, the direct driving force for benzoic acid Transport is suggested to be the inwardly directed proton gradient. From these results, together with previous observations using intestinal brush border membrane vesicles, the pH dependence of the transcellular Transport of certain organic weak acids across Caco-2 cells is considered to result mainly from a proton gradient-dependent, carrier-Mediated Transport mechanism, rather than passive diffusion according to the pH-partition theory.
David S Miller - One of the best experts on this subject based on the ideXlab platform.
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regulation of mrp2 Mediated Transport in shark rectal salt gland tubules
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2002Co-Authors: David S Miller, Rosalinde Masereeuw, Karl J KarnakyAbstract:We examined endothelin-1 (ET-1) regulation of the xenobiotic efflux pump, multidrug resistance-associated protein isoform 2 (MRP2), in intact dogfish shark rectal salt gland tubules using a fluores...
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nucleoside phosphonate interactions with multiple organic anion Transporters in renal proximal tubule
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: David S MillerAbstract:The interactions of two antiviral, acyclic nucleoside phosphonates, adefovir and cidofovir, with xenobiotic Transporters was studied in intact killifish ( Fundulus heteroclitus ) renal proximal tubules by using fluorescent substrates, confocal microscopy, and quantitative image analysis. Both drugs reduced in a concentration-dependent manner the Transport of fluorescein on the classical organic anion system and Transport of fluorescein-methotrexate on multidrug resistance-associated protein 2 (Mrp2). Neither drug inhibited Transport of a fluorescent cyclosporin A derivative on P-glycoprotein. Inhibition of Mrp2-Mediated Transport was abolished by 50 μM p -aminohippurate, indicating that adefovir and cidofovir entered the cells at the basolateral membrane on the classical organic anion Transport system (OAT1). Comparison of the inhibitory potencies of the nucleoside phosphonates with other substrates and inhibitors showed them to be moderate inhibitors of OAT1- and Mrp2-Mediated Transport.
Tetsuya Terasaki - One of the best experts on this subject based on the ideXlab platform.
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contribution of carrier Mediated Transport systems to the blood brain barrier as a supporting and protecting interface for the brain importance for cns drug discovery and development
Pharmaceutical Research, 2007Co-Authors: Sumio Ohtsuki, Tetsuya TerasakiAbstract:The blood-brain barrier (BBB) forms an interface between the circulating blood and the brain and possesses various carrier-Mediated Transport systems for small molecules to support and protect CNS function. For example, the blood-to-brain influx Transport systems supply nutrients, such as glucose and amino acids. Consequently, xenobiotic drugs recognized by influx Transporters are expected to have high permeability across the BBB. On the other hand, efflux Transporters, including ATP-binding cassette Transporters such as P-glycoprotein located at the luminal membrane of endothelial cells, function as clearance systems for metabolites and neurotoxic compounds produced in the brain. Drugs recognized by these Transporters are expected to show low BBB permeability and low distribution to the brain. Despite recent progress, the Transport mechanisms at the BBB have not been fully clarified yet, especially in humans. However, an understanding of the human BBB Transport system is critical, because species differences mean that it can be difficult to extrapolate data obtained in experimental animals during drug development to humans. Recent progress in methodologies is allowing us to address this issue. Positron emission tomography can be used to evaluate the activity of human BBB Transport systems in vivo. Proteomic studies may also provide important insights into human BBB function. Construction of a human BBB Transporter atlas would be a most important advance from the viewpoint of CNS drug discovery and drug delivery to the brain.
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transcellular Transport of benzoic acid across caco 2 cells by a ph dependent and carrier Mediated Transport mechanism
Pharmaceutical Research, 1994Co-Authors: Akira Tsuji, Hitomi Takanaga, Ikumi Tamai, Tetsuya TerasakiAbstract:The pH-dependent transcellular Transport of [14 C]benzoic acid across a Caco-2 cell monolayer is shown to be Mediated by a monocarboxylic acid-specific carrier-Mediated Transport system, localized on the apical membrane. Evidence for the carrier-Mediated Transport of benzoic acid includes (a) the significant temperature and concentration dependence, (b) the metabolic energy dependence, (c) the inhibition by unlabeled benzoic acid and other monocarboxylic acids, (d) counterTransport effects on the uptake of [14C]benzoic acid, and (e) effects of a proteinase (papain) and amino acid-modifying reagents. Furthermore, since carbonylcyanide p-trifluoromethoxyphenylhydrazone and nigericin significantly inhibited the Transport of [14C] benzoic acid, the direct driving force for benzoic acid Transport is suggested to be the inwardly directed proton gradient. From these results, together with previous observations using intestinal brush border membrane vesicles, the pH dependence of the transcellular Transport of certain organic weak acids across Caco-2 cells is considered to result mainly from a proton gradient-dependent, carrier-Mediated Transport mechanism, rather than passive diffusion according to the pH-partition theory.
Masayo Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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effects of fibrates on human organic anion Transporting polypeptide 1b1 multidrug resistance protein 2 and p glycoprotein Mediated Transport
Xenobiotica, 2005Co-Authors: Masayo Yamazaki, S W Louie, Nicole T Pudvah, R Stocco, W Wong, M Abramovitz, A Demartis, Ralph Laufer, Jerome H Hochman, Thomayant PrueksaritanontAbstract:The effects of different fibric acid derivatives (bezafibrate, clofibrate, clofibric acid, fenofibrate, fenofibric acid and gemfibrozil) on human organic anion Transporting-polypeptide 1B1 (OATP2, OATP-C, SLC21A6), multidrug resistance protein 2 (MRP2/ABCC2) and MDR1-type P-glycoprotein (P-gp/ABCB1) were examined in vitro. Cyclosporin A (a known inhibitor of OATP1B1 and P-gp), MK-571 (a known inhibitor of MRP2) and cimetidine (an organic cation) were also tested. Bezafibrate, fenofibrate, fenofibric acid and gemfibrozil showed concentration-dependent inhibition of estradiol 17-beta-D-glucuronide uptake by OATP1B1-stably transfected HEK cells, whereas clofibrate and clofibric acid did not show any significant effects up to 100 microM. Inhibition kinetics of gemfibrozil, which exhibited the most significant inhibition on OATP1B1, was shown to be competitive with a Ki = 12.5 microM. None of the fibrates showed any significant inhibition of MRP2-Mediated Transport, which was evaluated by measuring the uptake of ethacrynic acid glutathione into MRP2-expressing Sf9 membrane vesicles. Only fenofibrate showed moderate P-gp inhibition as assessed by measuring cellular accumulation of vinblastine in a P-gp overexpressing cell-line. Cyclosporin A significantly inhibited OATP1B1 and P-gp, whereas only moderate inhibition was observed on MRP2. The rank order of inhibitory potency of MK-571 was determined as OATP1B1 (IC50: 0.3 microM) > MRP2 (4 microM) > P-gp (25 microM). Cimetidine did not show any effects on these Transporters. In conclusion, neither MRP2- nor P-gp-Mediated Transport is inhibited significantly by the fibrates tested. Considering the plasma protein binding and IC50 values for OATP1B1, only gemfibrozil appeared to have a potential to cause drug-drug interactions by inhibiting OATP1B1 at clinically relevant concentrations.
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in vitro substrate identification studies for p glycoprotein Mediated Transport species difference and predictability of in vivo results
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Masayo Yamazaki, William E Neway, Tomoyuki Ohe, Iwu Chen, Janice Rowe, Jerome Hochman, Masato Chiba, Jiunn H LinAbstract:Two different cellular assay models were assessed as in vitro systems for P-glycoprotein (P-gp) substrate identification: cellular accumulation studies with KB-V1, a human MDR1 P-gp-overexpressing multidrug-resistant human epidermoid carcinoma cell line; and transcellular Transport studies with L-MDR1 (or L-mdr1a), a human MDR1 (or mouse mdr1a)-transfected porcine renal epithelial cell line. The in vitro-in vivo correlation for P-gp-Mediated Transport activity was also examined by comparing in vitro data obtained from L-mdr1a cell studies and in vivo data from mdr1a (-/-)/(+/+) CF-1 mice studies for several compounds. The results are summarized as follows: 1) two in vitro assay systems routinely identified the substrate for human MDR1 P-gp-Mediated Transport with similar quantitative results; 2) in vitro studies with L-MDR1 and L-mdr1a cells demonstrated that the P-gp substrate susceptibility is different between human and mouse for certain compounds (species difference); and 3) in vivo brain concentration ratios of mdr1a (-/-) to (+/+) CF-1 mice, either at a certain time point or up to 60 min, correlated well with the in vitro transcellular Transport ratios from L-mdr1a cells (r(2) = 0.968 and 0.926, respectively). This indicates that, at least in mice, the in vitro data are valid predictors of the in vivo contribution of P-gp: the contribution of P-gp to the distribution of the compound to the brain up to 60 min post i.v. administration. These results provide a rationale for predicting in vivo relevance of P-gp in human from in vitro data using human P-gp-expressing cells.
Thomayant Prueksaritanont - One of the best experts on this subject based on the ideXlab platform.
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effects of fibrates on human organic anion Transporting polypeptide 1b1 multidrug resistance protein 2 and p glycoprotein Mediated Transport
Xenobiotica, 2005Co-Authors: Masayo Yamazaki, S W Louie, Nicole T Pudvah, R Stocco, W Wong, M Abramovitz, A Demartis, Ralph Laufer, Jerome H Hochman, Thomayant PrueksaritanontAbstract:The effects of different fibric acid derivatives (bezafibrate, clofibrate, clofibric acid, fenofibrate, fenofibric acid and gemfibrozil) on human organic anion Transporting-polypeptide 1B1 (OATP2, OATP-C, SLC21A6), multidrug resistance protein 2 (MRP2/ABCC2) and MDR1-type P-glycoprotein (P-gp/ABCB1) were examined in vitro. Cyclosporin A (a known inhibitor of OATP1B1 and P-gp), MK-571 (a known inhibitor of MRP2) and cimetidine (an organic cation) were also tested. Bezafibrate, fenofibrate, fenofibric acid and gemfibrozil showed concentration-dependent inhibition of estradiol 17-beta-D-glucuronide uptake by OATP1B1-stably transfected HEK cells, whereas clofibrate and clofibric acid did not show any significant effects up to 100 microM. Inhibition kinetics of gemfibrozil, which exhibited the most significant inhibition on OATP1B1, was shown to be competitive with a Ki = 12.5 microM. None of the fibrates showed any significant inhibition of MRP2-Mediated Transport, which was evaluated by measuring the uptake of ethacrynic acid glutathione into MRP2-expressing Sf9 membrane vesicles. Only fenofibrate showed moderate P-gp inhibition as assessed by measuring cellular accumulation of vinblastine in a P-gp overexpressing cell-line. Cyclosporin A significantly inhibited OATP1B1 and P-gp, whereas only moderate inhibition was observed on MRP2. The rank order of inhibitory potency of MK-571 was determined as OATP1B1 (IC50: 0.3 microM) > MRP2 (4 microM) > P-gp (25 microM). Cimetidine did not show any effects on these Transporters. In conclusion, neither MRP2- nor P-gp-Mediated Transport is inhibited significantly by the fibrates tested. Considering the plasma protein binding and IC50 values for OATP1B1, only gemfibrozil appeared to have a potential to cause drug-drug interactions by inhibiting OATP1B1 at clinically relevant concentrations.