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PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers
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| Zeitschriftentitel: | Antimicrobial Agents and Chemotherapy |
|---|---|
| Personen und Körperschaften: | , , , |
| In: | Antimicrobial Agents and Chemotherapy, 46, 2002, 5, S. 1375-1380 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
|
| Schlagwörter: |
| author_facet |
Wenzel, Uwe Kuntz, Sabine Diestel, Simone Daniel, Hannelore Wenzel, Uwe Kuntz, Sabine Diestel, Simone Daniel, Hannelore |
|---|---|
| author |
Wenzel, Uwe Kuntz, Sabine Diestel, Simone Daniel, Hannelore |
| spellingShingle |
Wenzel, Uwe Kuntz, Sabine Diestel, Simone Daniel, Hannelore Antimicrobial Agents and Chemotherapy PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers Infectious Diseases Pharmacology (medical) Pharmacology |
| author_sort |
wenzel, uwe |
| spelling |
Wenzel, Uwe Kuntz, Sabine Diestel, Simone Daniel, Hannelore 0066-4804 1098-6596 American Society for Microbiology Infectious Diseases Pharmacology (medical) Pharmacology http://dx.doi.org/10.1128/aac.46.5.1375-1380.2002 <jats:title>ABSTRACT</jats:title> <jats:p> Ca <jats:sup>2+</jats:sup> channel blockers like nifedipine have been shown to increase the oral bioavailability of β-lactam antibiotics, such as cefixime, in humans. The molecular mode of action of Ca <jats:sup>2+</jats:sup> channel blockers on β-lactam absorption, however, has not yet been defined. Using the Caco-2 human intestinal epithelial cell line, we assessed whether alterations in intracellular free Ca <jats:sup>2+</jats:sup> ion (Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> ) concentrations by Ca <jats:sup>2+</jats:sup> channel blockers or by Ca <jats:sup>2+</jats:sup> ionophores affect [ <jats:sup>14</jats:sup> C]cefixime absorption. Reduction of Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by Ca <jats:sup>2+</jats:sup> channel blockers (nifedipine, verapamil, diltiazem, or bepridil) at concentrations of 100 μM led to 35 to 50% increases in the cellular uptake of 1 mM [ <jats:sup>14</jats:sup> C]cefixime. Increases in Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by Ca <jats:sup>2+</jats:sup> ionophores, on the other hand, led to 40% reductions in [ <jats:sup>14</jats:sup> C]cefixime absorption. Nifedipine increased the <jats:italic>V</jats:italic> <jats:sub>max</jats:sub> of cefixime transport by 67%, whereas the <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> of cefixime transport remained unaffected. By measuring the pH in Caco-2 cells loaded with the pH-sensitive fluorescent dye 2′,7′-bis(2-carboxyethyl)-5-(6)-carboxyfluorescein, we show that cefixime transport mediated by the intestinal H <jats:sup>+</jats:sup> -coupled peptide transporter PEPT1 leads to intracellular acidification. This acid load was reduced by nifedipine, although the Ca <jats:sup>2+</jats:sup> channel blocker increased the level of H <jats:sup>+</jats:sup> and cefixime cotransport. Increases in Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by ionomycin enhanced the decline in intracellular pH induced by cefixime alone, although ionomycin reduced the level of H <jats:sup>+</jats:sup> and cefixime cotransport. In conclusion, our studies demonstrate that alterations of Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels, e.g., by Ca <jats:sup>2+</jats:sup> channel blockers, affect pH regulatory systems, such as apical Na <jats:sup>+</jats:sup> and H <jats:sup>+</jats:sup> exchange, and thereby alter the H <jats:sup>+</jats:sup> gradient that serves as the driving force for uptake of β-lactams into intestinal epithelial cells. </jats:p> PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca <sup>2+</sup> Channel Blockers Antimicrobial Agents and Chemotherapy |
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American Society for Microbiology, 2002 |
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wenzel2002pept1mediatedcefiximeuptakeintohumanintestinalepithelialcellsisincreasedbyca2channelblockers |
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2002 |
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American Society for Microbiology |
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Antimicrobial Agents and Chemotherapy |
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49 |
| title |
PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_unstemmed |
PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_full |
PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_fullStr |
PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_full_unstemmed |
PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_short |
PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_sort |
pept1-mediated cefixime uptake into human intestinal epithelial cells is increased by ca
<sup>2+</sup>
channel blockers |
| topic |
Infectious Diseases Pharmacology (medical) Pharmacology |
| url |
http://dx.doi.org/10.1128/aac.46.5.1375-1380.2002 |
| publishDate |
2002 |
| physical |
1375-1380 |
| description |
<jats:title>ABSTRACT</jats:title>
<jats:p>
Ca
<jats:sup>2+</jats:sup>
channel blockers like nifedipine have been shown to increase the oral bioavailability of β-lactam antibiotics, such as cefixime, in humans. The molecular mode of action of Ca
<jats:sup>2+</jats:sup>
channel blockers on β-lactam absorption, however, has not yet been defined. Using the Caco-2 human intestinal epithelial cell line, we assessed whether alterations in intracellular free Ca
<jats:sup>2+</jats:sup>
ion (Ca
<jats:sup>2+</jats:sup>
<jats:sub>in</jats:sub>
) concentrations by Ca
<jats:sup>2+</jats:sup>
channel blockers or by Ca
<jats:sup>2+</jats:sup>
ionophores affect [
<jats:sup>14</jats:sup>
C]cefixime absorption. Reduction of Ca
<jats:sup>2+</jats:sup>
<jats:sub>in</jats:sub>
levels by Ca
<jats:sup>2+</jats:sup>
channel blockers (nifedipine, verapamil, diltiazem, or bepridil) at concentrations of 100 μM led to 35 to 50% increases in the cellular uptake of 1 mM [
<jats:sup>14</jats:sup>
C]cefixime. Increases in Ca
<jats:sup>2+</jats:sup>
<jats:sub>in</jats:sub>
levels by Ca
<jats:sup>2+</jats:sup>
ionophores, on the other hand, led to 40% reductions in [
<jats:sup>14</jats:sup>
C]cefixime absorption. Nifedipine increased the
<jats:italic>V</jats:italic>
<jats:sub>max</jats:sub>
of cefixime transport by 67%, whereas the
<jats:italic>
K
<jats:sub>m</jats:sub>
</jats:italic>
of cefixime transport remained unaffected. By measuring the pH in Caco-2 cells loaded with the pH-sensitive fluorescent dye 2′,7′-bis(2-carboxyethyl)-5-(6)-carboxyfluorescein, we show that cefixime transport mediated by the intestinal H
<jats:sup>+</jats:sup>
-coupled peptide transporter PEPT1 leads to intracellular acidification. This acid load was reduced by nifedipine, although the Ca
<jats:sup>2+</jats:sup>
channel blocker increased the level of H
<jats:sup>+</jats:sup>
and cefixime cotransport. Increases in Ca
<jats:sup>2+</jats:sup>
<jats:sub>in</jats:sub>
levels by ionomycin enhanced the decline in intracellular pH induced by cefixime alone, although ionomycin reduced the level of H
<jats:sup>+</jats:sup>
and cefixime cotransport. In conclusion, our studies demonstrate that alterations of Ca
<jats:sup>2+</jats:sup>
<jats:sub>in</jats:sub>
levels, e.g., by Ca
<jats:sup>2+</jats:sup>
channel blockers, affect pH regulatory systems, such as apical Na
<jats:sup>+</jats:sup>
and H
<jats:sup>+</jats:sup>
exchange, and thereby alter the H
<jats:sup>+</jats:sup>
gradient that serves as the driving force for uptake of β-lactams into intestinal epithelial cells.
</jats:p> |
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| description | <jats:title>ABSTRACT</jats:title> <jats:p> Ca <jats:sup>2+</jats:sup> channel blockers like nifedipine have been shown to increase the oral bioavailability of β-lactam antibiotics, such as cefixime, in humans. The molecular mode of action of Ca <jats:sup>2+</jats:sup> channel blockers on β-lactam absorption, however, has not yet been defined. Using the Caco-2 human intestinal epithelial cell line, we assessed whether alterations in intracellular free Ca <jats:sup>2+</jats:sup> ion (Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> ) concentrations by Ca <jats:sup>2+</jats:sup> channel blockers or by Ca <jats:sup>2+</jats:sup> ionophores affect [ <jats:sup>14</jats:sup> C]cefixime absorption. Reduction of Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by Ca <jats:sup>2+</jats:sup> channel blockers (nifedipine, verapamil, diltiazem, or bepridil) at concentrations of 100 μM led to 35 to 50% increases in the cellular uptake of 1 mM [ <jats:sup>14</jats:sup> C]cefixime. Increases in Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by Ca <jats:sup>2+</jats:sup> ionophores, on the other hand, led to 40% reductions in [ <jats:sup>14</jats:sup> C]cefixime absorption. Nifedipine increased the <jats:italic>V</jats:italic> <jats:sub>max</jats:sub> of cefixime transport by 67%, whereas the <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> of cefixime transport remained unaffected. By measuring the pH in Caco-2 cells loaded with the pH-sensitive fluorescent dye 2′,7′-bis(2-carboxyethyl)-5-(6)-carboxyfluorescein, we show that cefixime transport mediated by the intestinal H <jats:sup>+</jats:sup> -coupled peptide transporter PEPT1 leads to intracellular acidification. This acid load was reduced by nifedipine, although the Ca <jats:sup>2+</jats:sup> channel blocker increased the level of H <jats:sup>+</jats:sup> and cefixime cotransport. Increases in Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by ionomycin enhanced the decline in intracellular pH induced by cefixime alone, although ionomycin reduced the level of H <jats:sup>+</jats:sup> and cefixime cotransport. In conclusion, our studies demonstrate that alterations of Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels, e.g., by Ca <jats:sup>2+</jats:sup> channel blockers, affect pH regulatory systems, such as apical Na <jats:sup>+</jats:sup> and H <jats:sup>+</jats:sup> exchange, and thereby alter the H <jats:sup>+</jats:sup> gradient that serves as the driving force for uptake of β-lactams into intestinal epithelial cells. </jats:p> |
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| spelling | Wenzel, Uwe Kuntz, Sabine Diestel, Simone Daniel, Hannelore 0066-4804 1098-6596 American Society for Microbiology Infectious Diseases Pharmacology (medical) Pharmacology http://dx.doi.org/10.1128/aac.46.5.1375-1380.2002 <jats:title>ABSTRACT</jats:title> <jats:p> Ca <jats:sup>2+</jats:sup> channel blockers like nifedipine have been shown to increase the oral bioavailability of β-lactam antibiotics, such as cefixime, in humans. The molecular mode of action of Ca <jats:sup>2+</jats:sup> channel blockers on β-lactam absorption, however, has not yet been defined. Using the Caco-2 human intestinal epithelial cell line, we assessed whether alterations in intracellular free Ca <jats:sup>2+</jats:sup> ion (Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> ) concentrations by Ca <jats:sup>2+</jats:sup> channel blockers or by Ca <jats:sup>2+</jats:sup> ionophores affect [ <jats:sup>14</jats:sup> C]cefixime absorption. Reduction of Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by Ca <jats:sup>2+</jats:sup> channel blockers (nifedipine, verapamil, diltiazem, or bepridil) at concentrations of 100 μM led to 35 to 50% increases in the cellular uptake of 1 mM [ <jats:sup>14</jats:sup> C]cefixime. Increases in Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by Ca <jats:sup>2+</jats:sup> ionophores, on the other hand, led to 40% reductions in [ <jats:sup>14</jats:sup> C]cefixime absorption. Nifedipine increased the <jats:italic>V</jats:italic> <jats:sub>max</jats:sub> of cefixime transport by 67%, whereas the <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> of cefixime transport remained unaffected. By measuring the pH in Caco-2 cells loaded with the pH-sensitive fluorescent dye 2′,7′-bis(2-carboxyethyl)-5-(6)-carboxyfluorescein, we show that cefixime transport mediated by the intestinal H <jats:sup>+</jats:sup> -coupled peptide transporter PEPT1 leads to intracellular acidification. This acid load was reduced by nifedipine, although the Ca <jats:sup>2+</jats:sup> channel blocker increased the level of H <jats:sup>+</jats:sup> and cefixime cotransport. Increases in Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels by ionomycin enhanced the decline in intracellular pH induced by cefixime alone, although ionomycin reduced the level of H <jats:sup>+</jats:sup> and cefixime cotransport. In conclusion, our studies demonstrate that alterations of Ca <jats:sup>2+</jats:sup> <jats:sub>in</jats:sub> levels, e.g., by Ca <jats:sup>2+</jats:sup> channel blockers, affect pH regulatory systems, such as apical Na <jats:sup>+</jats:sup> and H <jats:sup>+</jats:sup> exchange, and thereby alter the H <jats:sup>+</jats:sup> gradient that serves as the driving force for uptake of β-lactams into intestinal epithelial cells. </jats:p> PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca <sup>2+</sup> Channel Blockers Antimicrobial Agents and Chemotherapy |
| spellingShingle | Wenzel, Uwe, Kuntz, Sabine, Diestel, Simone, Daniel, Hannelore, Antimicrobial Agents and Chemotherapy, PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers, Infectious Diseases, Pharmacology (medical), Pharmacology |
| title | PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_full | PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_fullStr | PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_full_unstemmed | PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_short | PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| title_sort | pept1-mediated cefixime uptake into human intestinal epithelial cells is increased by ca <sup>2+</sup> channel blockers |
| title_unstemmed | PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers |
| topic | Infectious Diseases, Pharmacology (medical), Pharmacology |
| url | http://dx.doi.org/10.1128/aac.46.5.1375-1380.2002 |