Abstract
The effect of cytochrome P-450 3A (CYP3A) substrates (erythromycin, midazolam) and an inhibitor (ketoconazole) on P-glycoprotein-mediated transport was studied in Caco-2, the human colon adenocarcinoma cell line expressing various functions of differentiated intestinal epithelial cells. The involvement of P-glycoprotein in the transport of these drugs was also examined. The basal-to-apical transport of rhodamine 123, a P-glycoprotein substrate, was inhibited by erythromycin, midazolam and ketoconazole, as well as by P-glycoprotein inhibitors such as verapamil. The apical-to-basal transport of rhodamine 123 was increased by these drugs. The transepithelial transport of erythromycin and midazolam, but not of ketoconazole, was much greater from the basal to apical side than from the apical to basal side. The inhibitory effect of verapamil was observed on the basal to apical transport of erythromycin, but not on midazolam and ketoconazole transport. In conclusion, erythromycin, midazolam and ketoconazole could interact with P-glycoprotein-mediated transport, and P-glycoprotein could be, at least in part, involved in the transport of erythromycin, but not of midazolam and ketoconazole, in the intestinal epithelia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / physiology*
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Anti-Bacterial Agents / pharmacokinetics
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Anti-Bacterial Agents / pharmacology
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Antifungal Agents / pharmacokinetics
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Antifungal Agents / pharmacology
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Aryl Hydrocarbon Hydroxylases*
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Biological Transport / drug effects
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Biological Transport / physiology
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Caco-2 Cells / drug effects
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Caco-2 Cells / metabolism
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism
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Enzyme Inhibitors / pharmacology
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Erythromycin / pharmacokinetics
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Erythromycin / pharmacology*
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GABA Modulators / pharmacokinetics
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GABA Modulators / pharmacology
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Humans
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Ketoconazole / pharmacokinetics
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Ketoconazole / pharmacology*
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Midazolam / pharmacokinetics
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Midazolam / pharmacology*
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Oxidoreductases, N-Demethylating / antagonists & inhibitors
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Oxidoreductases, N-Demethylating / metabolism
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Rhodamine 123 / antagonists & inhibitors
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Rhodamine 123 / pharmacokinetics
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Substrate Specificity
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Vasodilator Agents / pharmacology
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Verapamil / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B
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Anti-Bacterial Agents
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Antifungal Agents
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Cytochrome P-450 Enzyme Inhibitors
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Enzyme Inhibitors
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GABA Modulators
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Vasodilator Agents
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Rhodamine 123
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Erythromycin
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Cytochrome P-450 Enzyme System
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Verapamil
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP3A
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Oxidoreductases, N-Demethylating
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Midazolam
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Ketoconazole