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Katsumi Miyazaki - One of the best experts on this subject based on the ideXlab platform.
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the inhibitory effects of cephalosporin and dipeptide on Ceftibuten uptake by human and rat intestinal brush border membrane vesicles
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Katsumi Miyazaki, Ken Iseki, Takaki Toda, Hiroshi Shiroto, Junichi Uchino, Michiya Kobayashi, Yukifumi KondoAbstract:The types of inhibitory effects caused by compound V (an analogue of Ceftibuten) and alanylproline (dipeptide) on the uptake of Ceftibuten by brush-border membrane vesicles (BBMV) prepared from human and rat small intestine were analysed. In the presence of an inward H(+)-gradient, the initial uptake rate of Ceftibuten by both human and rat intestinal BBMV was concentration-dependent with apparent Km and Vmax values of 0.35 mM and 2.052 nmol (mg protein)-1 min-1 for human BBMV, and 0.50 mM and 3.056 nmol (mg protein)-1 min-1 for rat BBMV, respectively. For both human and rat BBMV, kinetic analysis by Dixon and Lineweaver-Burk plots demonstrated that the uptake of Ceftibuten was competitively inhibited by compound V, whereas inhibition by alanylproline was noncompetitive or partially competitive. These results suggest that there is a stereospecific transport system which is common to Ceftibuten and compound V, and that this system is not identical to the carrier system for the dipeptide, alanylproline.
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h coupled transport of orally active cephalosporins lacking an α amino group across brush border membrane vesicles from rat small intestine
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Ken Iseki, Katsumi MiyazakiAbstract:— The effect of an inwardly directed H+ gradient on the transport characteristics of Ceftibuten, cefixime and analogues of Ceftibuten in rat intestinal brush-border membrane vesicles have been investigated. In the presence of a transmembrane H+ gradient, Ceftibuten and its analogues exhibited a peak to equilibrium overshoot and an accumulation in the vesicles against the concentration gradient. However, the uptake of cefixime and S-1006 [(6R, 7R)-(7-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-8-oxo-3-carba-moyloxy-methyl-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid), which lacks a carboxyl group at position 4 of carboxyethylidene structure, exhibited no overshoot, although the equilibrium uptake was increased by a H+ gradient. The equilibrium uptake was dependent on the pH of the final incubation medium and the H + gradient. These data suggested that the orally active cephalosporins were transported into rat intestinal brush-border membrane by the transmembrane H+ gradient and the pH of the medium.
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transport characteristics of Ceftibuten cefixime and cephalexin across human jejunal brush border membrane
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Katsumi Miyazaki, Ken Iseki, Hiroshi Shiroto, Yukifumi Kondo, Junichi UchinoAbstract:The transport characteristics of orally active cephalosporins, Ceftibuten, cefixime and cephalexin have been examined using brush border membrane vesicles isolated from human jejunum. In the initial uptake of Ceftibuten, the stimulation and overshoot phenomena were observed in the presence of an inward H+ gradient. Effects of H+ gradient on the uptake of cefixime and cephalexin were low and no overshoot was observed. These transport characteristics, especially uphill transport phenomena, were in agreement with previous results obtained from rat intestinal brush-border membrane vesicles and suggest that these beta-lactam antibiotics are absorbed by different transport systems, despite their similar molecular structures.
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multiplicity of the h dependent transport mechanism of dipeptide and anionic β lactam antibiotic Ceftibuten in rat intestinal brush border membrane
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Ken Iseki, Mitsuru Sugawara, Kaori Sato, Imad Naasani, Tomohisa Hayakawa, Michiya Kobayashi, Katsumi MiyazakiAbstract:To elucidate the transport characteristics of the H+/dipeptide carrier that recognizes the orally active β-lactam antibiotic Ceftibuten, the uptake behaviors were compared of Ceftibuten and Gly-Sar by rat intestinal brush-border membrane vesicles. The results show that 1) both the uptake of Ceftibuten and that of Gly-Sar were dependent on an inwardly directed H+gradient; 2) anionic compounds such as hippurylphenyllactic acid competitively inhibited Ceftibuten uptake in the presence of H+ gradient, whereas this anion did not inhibit Gly-Sar uptake; and 3) the carrier-mediated uptake of Ceftibuten did not disappear even in the presence of 20 mM Gly-Sar. The results provide an evidence that several transporters with different features are potentially responsible for the uptake of β-lactam antibiotics into the intestinal cells. It is suggested that the dianionic β-lactam antibiotics that carry a net negative charge such as Ceftibuten use multiple H+-dependent transport systems for absorption.
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purification by Ceftibuten affinity chromatography and the functional reconstitution of oligopeptide transporter s in rat intestinal brush border membrane
Biochimica et Biophysica Acta, 1998Co-Authors: Ken Iseki, Mitsuru Sugawara, Imad Naasani, Michiya Kobayashi, Takayuki Kikuchi, Naonori Kohri, Kazuhiro Yonemura, Katsumi MiyazakiAbstract:Abstract The transport activity of Ceftibuten, a dianionic peptide-like compound, was extracted from rat intestinal brush-border membrane by n -octylglucoside and reconstituted into asolectin liposomes by dialysis. The proteoliposomes prepared from the membrane extract showed an inward H + -gradient-dependent uptake of Ceftibuten and glycylsarcosine. Ceftibuten-immobilized affinity chromatography of the membrane extract permitted the isolation of two polypeptides (apparent molecular mass of 117 and 127 kDa) that can recognize the dianionic peptide structure of Ceftibuten. Proteoliposomes prepared from reconstituting the isolated proteins into asolectin vesicles showed an overshooting uptake of Ceftibuten in the presence of an inwardly directed H + gradient, and this uptake could be inhibited by l -valyl- l -proline. N -glycanase digestion of the isolated proteins, 117 and 127 kDa, trimmed them into 78 and 120 kDa products, respectively. The protein core size of the smaller protein was in agreement with the calculated molecular mass of ∼79 kDa for the rat PepT1 transporter obtained by other investigators.
Ken Iseki - One of the best experts on this subject based on the ideXlab platform.
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the inhibitory effects of cephalosporin and dipeptide on Ceftibuten uptake by human and rat intestinal brush border membrane vesicles
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Katsumi Miyazaki, Ken Iseki, Takaki Toda, Hiroshi Shiroto, Junichi Uchino, Michiya Kobayashi, Yukifumi KondoAbstract:The types of inhibitory effects caused by compound V (an analogue of Ceftibuten) and alanylproline (dipeptide) on the uptake of Ceftibuten by brush-border membrane vesicles (BBMV) prepared from human and rat small intestine were analysed. In the presence of an inward H(+)-gradient, the initial uptake rate of Ceftibuten by both human and rat intestinal BBMV was concentration-dependent with apparent Km and Vmax values of 0.35 mM and 2.052 nmol (mg protein)-1 min-1 for human BBMV, and 0.50 mM and 3.056 nmol (mg protein)-1 min-1 for rat BBMV, respectively. For both human and rat BBMV, kinetic analysis by Dixon and Lineweaver-Burk plots demonstrated that the uptake of Ceftibuten was competitively inhibited by compound V, whereas inhibition by alanylproline was noncompetitive or partially competitive. These results suggest that there is a stereospecific transport system which is common to Ceftibuten and compound V, and that this system is not identical to the carrier system for the dipeptide, alanylproline.
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h coupled transport of orally active cephalosporins lacking an α amino group across brush border membrane vesicles from rat small intestine
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Ken Iseki, Katsumi MiyazakiAbstract:— The effect of an inwardly directed H+ gradient on the transport characteristics of Ceftibuten, cefixime and analogues of Ceftibuten in rat intestinal brush-border membrane vesicles have been investigated. In the presence of a transmembrane H+ gradient, Ceftibuten and its analogues exhibited a peak to equilibrium overshoot and an accumulation in the vesicles against the concentration gradient. However, the uptake of cefixime and S-1006 [(6R, 7R)-(7-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-8-oxo-3-carba-moyloxy-methyl-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid), which lacks a carboxyl group at position 4 of carboxyethylidene structure, exhibited no overshoot, although the equilibrium uptake was increased by a H+ gradient. The equilibrium uptake was dependent on the pH of the final incubation medium and the H + gradient. These data suggested that the orally active cephalosporins were transported into rat intestinal brush-border membrane by the transmembrane H+ gradient and the pH of the medium.
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transport characteristics of Ceftibuten cefixime and cephalexin across human jejunal brush border membrane
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Katsumi Miyazaki, Ken Iseki, Hiroshi Shiroto, Yukifumi Kondo, Junichi UchinoAbstract:The transport characteristics of orally active cephalosporins, Ceftibuten, cefixime and cephalexin have been examined using brush border membrane vesicles isolated from human jejunum. In the initial uptake of Ceftibuten, the stimulation and overshoot phenomena were observed in the presence of an inward H+ gradient. Effects of H+ gradient on the uptake of cefixime and cephalexin were low and no overshoot was observed. These transport characteristics, especially uphill transport phenomena, were in agreement with previous results obtained from rat intestinal brush-border membrane vesicles and suggest that these beta-lactam antibiotics are absorbed by different transport systems, despite their similar molecular structures.
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nateglinide uptake by a Ceftibuten transporter in the rat kidney brush border membrane
Biochimica et Biophysica Acta, 2005Co-Authors: Masaki Kobayashi, Yoshitaka Saito, Shirou Itagaki, Takeshi Hirano, Ken IsekiAbstract:Nateglinide, a novel oral hypoglycemic agent, possesses a carbonyl group and a peptide-type bond in its structure. We previously reported that nateglinide transport occurs via a single system that may be identical to the Ceftibuten/H(+) cotransport system by the rat small intestine. We speculated that the absorption system present on the intestinal epithelium may be similar to that found on the renal tubular epithelium. The aim of this study was to characterize the transporters on the apical side of the kidney that may contribute to the reabsorption of Ceftibuten and nateglinide. The uptake of nateglinide by rat renal brush-border membranes is associated with an H(+)-coupled transport system. Ceftibuten competitively inhibited H(+)-dependent nateglinide uptake. In contrast, Gly-Sar, cephradine and cephalexin had no effect on nateglinide uptake. Nateglinide competitively inhibited H(+)-driven transporter-mediated Ceftibuten uptake. We conclude that nateglinide transport occurs via a single system that is H(+)-dependent and may be identical to the Ceftibuten/H(+) cotransport system.
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h dependent transport mechanism of nateglinide in the brush border membrane of the rat intestine
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Shirou Itagaki, Yoshitaka Saito, Sayaka Kubo, Yukio Otsuka, Yuta Yamamoto, Masaki Kobayashi, Takeshi Hirano, Ken IsekiAbstract:(-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) is a novel oral hypoglycemic agent possessing a carboxyl group and a peptide-type bond in its structure. Although nateglinide quickly reaches the maximal serum concentration after oral administration, nateglinide itself is not transported by PepT1 or MCT1. The aim of this study was to characterize the transporters on the apical side of the small intestine that are responsible for the rapid absorption of nateglinide. The uptake of nateglinide by rat intestinal brush-border membrane vesicles is associated with a proton-coupled transport system. Ceftibuten competitively inhibited H(+)-dependent nateglinide uptake. Glycylsarcosine (Gly-Sar), cephradine, and cephalexin did not significantly inhibit the uptake of nateglinide. The combination of Gly-Sar and nateglinide greatly reduced the uptake of Ceftibuten. The effect of the combined treatment was significantly greater than that of Gly-Sar alone. Furthermore, nateglinide competitively inhibited H(+)-driven Ceftibuten transporter-mediated Ceftibuten uptake. Ceftibuten transport occurs via at least two H(+)-dependent transport systems: one is PepT1, and the other is the Ceftibuten/H(+) cotransport system. On the other hand, we demonstrated that nateglinide transport occurs via a single system that is H(+) dependent but is distinct from PepT1 and may be identical to the Ceftibuten/H(+) cotransport system.
Mitsuru Sugawara - One of the best experts on this subject based on the ideXlab platform.
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the inhibitory effects of cephalosporin and dipeptide on Ceftibuten uptake by human and rat intestinal brush border membrane vesicles
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Katsumi Miyazaki, Ken Iseki, Takaki Toda, Hiroshi Shiroto, Junichi Uchino, Michiya Kobayashi, Yukifumi KondoAbstract:The types of inhibitory effects caused by compound V (an analogue of Ceftibuten) and alanylproline (dipeptide) on the uptake of Ceftibuten by brush-border membrane vesicles (BBMV) prepared from human and rat small intestine were analysed. In the presence of an inward H(+)-gradient, the initial uptake rate of Ceftibuten by both human and rat intestinal BBMV was concentration-dependent with apparent Km and Vmax values of 0.35 mM and 2.052 nmol (mg protein)-1 min-1 for human BBMV, and 0.50 mM and 3.056 nmol (mg protein)-1 min-1 for rat BBMV, respectively. For both human and rat BBMV, kinetic analysis by Dixon and Lineweaver-Burk plots demonstrated that the uptake of Ceftibuten was competitively inhibited by compound V, whereas inhibition by alanylproline was noncompetitive or partially competitive. These results suggest that there is a stereospecific transport system which is common to Ceftibuten and compound V, and that this system is not identical to the carrier system for the dipeptide, alanylproline.
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h coupled transport of orally active cephalosporins lacking an α amino group across brush border membrane vesicles from rat small intestine
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Ken Iseki, Katsumi MiyazakiAbstract:— The effect of an inwardly directed H+ gradient on the transport characteristics of Ceftibuten, cefixime and analogues of Ceftibuten in rat intestinal brush-border membrane vesicles have been investigated. In the presence of a transmembrane H+ gradient, Ceftibuten and its analogues exhibited a peak to equilibrium overshoot and an accumulation in the vesicles against the concentration gradient. However, the uptake of cefixime and S-1006 [(6R, 7R)-(7-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-8-oxo-3-carba-moyloxy-methyl-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid), which lacks a carboxyl group at position 4 of carboxyethylidene structure, exhibited no overshoot, although the equilibrium uptake was increased by a H+ gradient. The equilibrium uptake was dependent on the pH of the final incubation medium and the H + gradient. These data suggested that the orally active cephalosporins were transported into rat intestinal brush-border membrane by the transmembrane H+ gradient and the pH of the medium.
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transport characteristics of Ceftibuten cefixime and cephalexin across human jejunal brush border membrane
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Mitsuru Sugawara, Katsumi Miyazaki, Ken Iseki, Hiroshi Shiroto, Yukifumi Kondo, Junichi UchinoAbstract:The transport characteristics of orally active cephalosporins, Ceftibuten, cefixime and cephalexin have been examined using brush border membrane vesicles isolated from human jejunum. In the initial uptake of Ceftibuten, the stimulation and overshoot phenomena were observed in the presence of an inward H+ gradient. Effects of H+ gradient on the uptake of cefixime and cephalexin were low and no overshoot was observed. These transport characteristics, especially uphill transport phenomena, were in agreement with previous results obtained from rat intestinal brush-border membrane vesicles and suggest that these beta-lactam antibiotics are absorbed by different transport systems, despite their similar molecular structures.
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multiplicity of the h dependent transport mechanism of dipeptide and anionic β lactam antibiotic Ceftibuten in rat intestinal brush border membrane
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Ken Iseki, Mitsuru Sugawara, Kaori Sato, Imad Naasani, Tomohisa Hayakawa, Michiya Kobayashi, Katsumi MiyazakiAbstract:To elucidate the transport characteristics of the H+/dipeptide carrier that recognizes the orally active β-lactam antibiotic Ceftibuten, the uptake behaviors were compared of Ceftibuten and Gly-Sar by rat intestinal brush-border membrane vesicles. The results show that 1) both the uptake of Ceftibuten and that of Gly-Sar were dependent on an inwardly directed H+gradient; 2) anionic compounds such as hippurylphenyllactic acid competitively inhibited Ceftibuten uptake in the presence of H+ gradient, whereas this anion did not inhibit Gly-Sar uptake; and 3) the carrier-mediated uptake of Ceftibuten did not disappear even in the presence of 20 mM Gly-Sar. The results provide an evidence that several transporters with different features are potentially responsible for the uptake of β-lactam antibiotics into the intestinal cells. It is suggested that the dianionic β-lactam antibiotics that carry a net negative charge such as Ceftibuten use multiple H+-dependent transport systems for absorption.
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purification by Ceftibuten affinity chromatography and the functional reconstitution of oligopeptide transporter s in rat intestinal brush border membrane
Biochimica et Biophysica Acta, 1998Co-Authors: Ken Iseki, Mitsuru Sugawara, Imad Naasani, Michiya Kobayashi, Takayuki Kikuchi, Naonori Kohri, Kazuhiro Yonemura, Katsumi MiyazakiAbstract:Abstract The transport activity of Ceftibuten, a dianionic peptide-like compound, was extracted from rat intestinal brush-border membrane by n -octylglucoside and reconstituted into asolectin liposomes by dialysis. The proteoliposomes prepared from the membrane extract showed an inward H + -gradient-dependent uptake of Ceftibuten and glycylsarcosine. Ceftibuten-immobilized affinity chromatography of the membrane extract permitted the isolation of two polypeptides (apparent molecular mass of 117 and 127 kDa) that can recognize the dianionic peptide structure of Ceftibuten. Proteoliposomes prepared from reconstituting the isolated proteins into asolectin vesicles showed an overshooting uptake of Ceftibuten in the presence of an inwardly directed H + gradient, and this uptake could be inhibited by l -valyl- l -proline. N -glycanase digestion of the isolated proteins, 117 and 127 kDa, trimmed them into 78 and 120 kDa products, respectively. The protein core size of the smaller protein was in agreement with the calculated molecular mass of ∼79 kDa for the rat PepT1 transporter obtained by other investigators.
Chinchung Lin - One of the best experts on this subject based on the ideXlab platform.
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the penetration of Ceftibuten into the respiratory tract
Chest, 1999Co-Authors: Peter Krumpe, Chinchung Lin, Elaine Radwanski, Mitchell N Cayen, Melton B AffrimeAbstract:Study objective To determine the penetration of Ceftibuten into various respiratory tissues and fluids. Design Single-dose, open-label, pharmacokinetic study. Setting Veterans Administration Medical Center. Patients Twelve hospitalized men aged 34 to 75 years with a variety of noninfectious pulmonary symptoms/diseases. Interventions Patients received a single oral dose of Ceftibuten, 200 mg, prior to undergoing diagnostic fiberoptic bronchoscopy. Plasma samples for the determination of Ceftibuten concentrations were collected pretreatment and up to 12 h postdosing. Nasal secretions, tracheal secretions, BAL fluid, and lung tissue from a biopsy were obtained at bronchoscopy from 2 to 7 h postdosing. Measurements and results Mean pharmacokinetic parameters for Ceftibuten in plasma were the following: maximum observed plasma concentration (Cmax), 8.77 μg/mL; time to reach Cmax, 2.2 h; area under the plasma concentration-time curve extraploated to infinity, 49.21 μg/h/mL; and terminal elimination half-life, 3.17 h. These parameters were similar to those obtained in studies using healthy volunteers. Mean penetration of Ceftibuten into nasal, tracheal, and bronchial secretions was 47%, 50%, and 30%, respectively. Mean penetration into BAL fluid was 81%, whereas penetration into lung tissue was 39%. No patient experienced any adverse effects related to Ceftibuten. Conclusions Ceftibuten penetrates well into various tissues and fluids of the upper and lower respiratory tracts. The results support the activity of Ceftibuten in the treatment of upper and lower respiratory tract infections.
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multiple dose pharmacokinetics of Ceftibuten in healthy volunteers
Antimicrobial Agents and Chemotherapy, 1995Co-Authors: Chinchung Lin, Melton B Affrime, Elaine Radwanski, Mitchell N CayenAbstract:The pharmacokinetics of Ceftibuten, a new cephalosporin antibiotic, and its conversion product, Ceftibutentrans, were studied in healthy male volunteers following daily oral administration of a 400-mg capsule for 7 days. Mean concentrations of Ceftibuten in plasma obtained on day 5 were similar to those obtained on day 7. Analysis of variance indicated that the concentrations in plasma on days 5 and 7 were at steady state. The mean accumulation factor was 1.14 for day 5 and 1.13 for day 7. The half-life (2.4 h) was independent of the duration of drug administration, and the mean maximum concentration of drug in plasma was 18 to 19 micrograms/ml. Urinary excretion was the major elimination route for Ceftibuten, by which 57 to 59% of the drug was excreted unchanged over a 24-h period. The amounts of Ceftibuten-trans in plasma and urine were low.
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liquid chromatographic determination of Ceftibuten a new oral cephalosporin in human plasma and urine
Journal of Pharmaceutical and Biomedical Analysis, 1994Co-Authors: Josephine Lim, Hong Kim, Aliceann Marco, Parviz Mojaverian, Chinchung LinAbstract:Two liquid chromatographic methods with UV detection were developed for the determination of Ceftibuten in human plasma and urine. Diluted plasma samples were directly injected onto a reversed-phase column without prior protein precipitation while diluted urine samples were processed through an automated on-line sample clean-up procedure using column-switching. Both methods were linear over clinically relevant concentration ranges in plasma (from 0.1 to 50 μg ml−1) and urine (from 0.5 to 60 μg ml−1). The methods showed acceptable precision (RSD <20%) and accuracy (bias <15%) at the limit of quantitation (LOQ) for Ceftibuten in plasma and urine. These LOQs represented the lowest concentrations of Ceftibuten in plasma (0.1 μg ml−1) and urine (0.5 μg ml−1) that could be measured with acceptable precision and accuracy. RSDs for both within-day and between-day analyses were ≤12% for plasma and <7% for urine. These methods have been used successfully for the analysis of Ceftibuten in plasma and urine following single oral doses of 200, 400 and 800 mg in man.
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determination of Ceftibuten in sputum by column switching high performance liquid chromatography on line with thermospray mass spectrometry
Journal of Pharmaceutical Sciences, 1993Co-Authors: Hwaitzong Pan, Pramila Kumari, Arthur J F De Silva, Chinchung LinAbstract:Abstract A column-switching high-performance liquid chromato-graphic assay on-line with thermospray mass spectrometric detection is described for the determination of Ceftibuten, an oral cephalosporin antibiotic, in human sputum. The method does not require sample pretreatment and provides increased selectivity not available from the previously reported method with UV detection. The thermospray mass spectrometric detection conditions were optimized for Ceftibuten. The technique has a detection limit of 0.50 μg/mL and allows precise, simple, and accurate determination of Ceftibuten in sputum over the range 0.50–10.00 μg/mL.
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determination of a cephalosporin antibiotic Ceftibuten in human plasma with column switching high performance liquid chromatography with ultraviolet detection
Journal of Pharmaceutical Sciences, 1992Co-Authors: Hwaitzong Pan, Pramila Kumari, Josephine Lim, Chinchung LinAbstract:A column-switching high-performance liquid chromatographic assay combined with a heart-cutting technique and UV detection (LC/LC/UV) was developed to determine Ceftibuten, a new oral cephalosporin, in human plasma. Plasma samples were directly injected into the first chromatographic column for sample cleanup and extraction. Thereafter, a switching valve, located at the junction of the first cleanup column and the second analytical column, opened during a 4-6-min interval after injection to transfer the segment containing Ceftibuten into the analytical column for quantitation. The method was used routinely in pharmacokinetic studies and has the advantages of simplicity, improved sensitivity, and selectivity. Concentrations of Ceftibuten in plasma over a range of 0.1-20 micrograms/mL can be determined with high precision and reproducibility. A single, oral, 200-mg dose of Ceftibuten in humans resulted in a maximum concentration of 9.79 micrograms/mL, an area under the plot of concentration of drug in plasma versus time (0-12 h) of 47.77 micrograms.h/mL, and a half-life of 3.2 h. These results document the utility of the LC/LC/UV method in clinical pharmacokinetic studies.
Imad Naasani - One of the best experts on this subject based on the ideXlab platform.
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multiplicity of the h dependent transport mechanism of dipeptide and anionic β lactam antibiotic Ceftibuten in rat intestinal brush border membrane
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Ken Iseki, Mitsuru Sugawara, Kaori Sato, Imad Naasani, Tomohisa Hayakawa, Michiya Kobayashi, Katsumi MiyazakiAbstract:To elucidate the transport characteristics of the H+/dipeptide carrier that recognizes the orally active β-lactam antibiotic Ceftibuten, the uptake behaviors were compared of Ceftibuten and Gly-Sar by rat intestinal brush-border membrane vesicles. The results show that 1) both the uptake of Ceftibuten and that of Gly-Sar were dependent on an inwardly directed H+gradient; 2) anionic compounds such as hippurylphenyllactic acid competitively inhibited Ceftibuten uptake in the presence of H+ gradient, whereas this anion did not inhibit Gly-Sar uptake; and 3) the carrier-mediated uptake of Ceftibuten did not disappear even in the presence of 20 mM Gly-Sar. The results provide an evidence that several transporters with different features are potentially responsible for the uptake of β-lactam antibiotics into the intestinal cells. It is suggested that the dianionic β-lactam antibiotics that carry a net negative charge such as Ceftibuten use multiple H+-dependent transport systems for absorption.
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purification by Ceftibuten affinity chromatography and the functional reconstitution of oligopeptide transporter s in rat intestinal brush border membrane
Biochimica et Biophysica Acta, 1998Co-Authors: Ken Iseki, Mitsuru Sugawara, Imad Naasani, Michiya Kobayashi, Takayuki Kikuchi, Naonori Kohri, Kazuhiro Yonemura, Katsumi MiyazakiAbstract:Abstract The transport activity of Ceftibuten, a dianionic peptide-like compound, was extracted from rat intestinal brush-border membrane by n -octylglucoside and reconstituted into asolectin liposomes by dialysis. The proteoliposomes prepared from the membrane extract showed an inward H + -gradient-dependent uptake of Ceftibuten and glycylsarcosine. Ceftibuten-immobilized affinity chromatography of the membrane extract permitted the isolation of two polypeptides (apparent molecular mass of 117 and 127 kDa) that can recognize the dianionic peptide structure of Ceftibuten. Proteoliposomes prepared from reconstituting the isolated proteins into asolectin vesicles showed an overshooting uptake of Ceftibuten in the presence of an inwardly directed H + gradient, and this uptake could be inhibited by l -valyl- l -proline. N -glycanase digestion of the isolated proteins, 117 and 127 kDa, trimmed them into 78 and 120 kDa products, respectively. The protein core size of the smaller protein was in agreement with the calculated molecular mass of ∼79 kDa for the rat PepT1 transporter obtained by other investigators.
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purification and liposomal reconstitution of the oligopeptide transport activity in rat renal cortex using Ceftibuten affinity chromatography
Biochimica et Biophysica Acta, 1998Co-Authors: Ken Iseki, Mitsuru Sugawara, Imad Naasani, Michiya Kobayashi, Takayuki Kikuchi, Naonori Kohri, Katsumi MiyazakiAbstract:The carrier protein(s) responsible for the transport of Ceftibuten, a peptide-like dianionic cefem, in rat renal brush-border membrane were solubilized and purified by a Ceftibuten-ligand specific affinity chromatography technique. The proteoliposomes reconstituted from the solubilized brush-border membrane proteins by dialysis had H+-sensitive uptake of Ceftibuten and trans-stimulative effect by cephalexin. A specific uptake activity for Ceftibuten was found in the 3.5 M-eluted fraction but not the flowthrough and the 0.5 M-eluted fraction of the affinity chromatography. Analyzing this active fraction by SDS/PAGE after reconstituting into liposomes gave two major proteins (approx. molecular masses of 130 and 107 kDa). The purification protocol presented in this study permitted an efficient isolation of the carrier proteins responsible for the transport of Ceftibuten and other peptide-like compounds.
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Comparison of the transport characteristics of Ceftibuten in rat renal and intestinal brush-border membranes.
Biochimica et biophysica acta, 1995Co-Authors: Imad Naasani, Mitsuru Sugawara, Ken Iseki, Kaori Sato, Michiya Kobayashi, Katsumi MiyazakiAbstract:The transport characteristics of Ceftibuten, a dianionic cephem antibiotic, in rat renal and intestinal brush-border membranes were compared. Ceftibuten transport was mediated by two transport systems in the renal brush-border membrane and by one transport system in the intestinal brush-border membrane. The apparent kinetic parameters for the uptake of Ceftibuten by the renal brush-border membrane vesicles, respectively, were: Km1, Km2 values of 26 and 1946 microM and Vmax1, Vmax2 values of 105 and 1400 pmol/mg protein per 30 s. The apparent kinetic parameters for the uptake by the intestinal brush-border membrane vesicles were: Km of 425 microM and Vmax of 1701 pmol/mg protein per 30 s. In the renal brush-border membrane, L-Ala-L-Pro was partially competitive and competitive inhibitor for the uptake by the high and low affinity systems, respectively. However, L-Ala-L-Pro was a non-competitive inhibitor for the uptake by the intestinal brush-border membrane vesicles. L-Carnosine was a specific and competitive inhibitor for the high affinity system in the renal brush-border membrane, while it had no effect on the low affinity system of the kidney or on the transport system of the intestine. It was concluded that the transport characteristics of Ceftibuten in the renal and intestinal brush-border membranes are similar in some aspects but they are not identical.
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transport mechanism of Ceftibuten a dianionic cephem in rat renal brush border membrane
Pharmaceutical Research, 1995Co-Authors: Imad Naasani, Mitsuru Sugawara, Ken Iseki, Michiya Kobayashi, Katsumi MiyazakiAbstract:The uptake mechanism of Ceftibuten by rat renal brush-border membrane vesicles was investigated. Uptake was found to be independent of a Na+ gradient and partially dependent on an inwardly directed H +-gradient. Competition experiments between Ceftibuten and several compounds demonstrated that the peptide-like structural features of inhibitors are more essential than their charge properties for inhibiting uptake. Anionic compound, such as p-amino-hippuric acid, also inhibited Ceftibuten uptake by renal brush-border membrane vesicles in the presence of an H +-gradient. We conclude that Ceftibuten, in spite of its anionic structure, is transported via the dipeptide transport systems, rather than the organic anion transport system.