Enhancing the permeation of marker compounds and enaminone anticonvulsants across Caco-2 monolayers by modulating tight junctions using zonula occludens toxin.
Zonula occludens toxin (Zot), a protein elaborated from Vibrio cholerae, has been shown to be capable of reversibly opening tight junctions between intestinal cells The objective of this study was to examine the effect of Zot on the flux of various molecules across Caco-2 cell monolayers. In addition, the transport of a series of anticonvulsants, the enaminones was also evaluated in the presence of Zot. The flux of [(14)C]mannitol, [(14)C]inulin and various enaminones across Caco-2 cell monolayers (n=6) was examined after pre-incubation for 1h with Zot (0 or 4000ng/ml) or phosphate-buffered saline (PBS). At the end of the incubation period, the flux of radiolabeled compounds or enaminones (1x10(-4)M) was assessed over a 2-h period. In addition, dose-response studies with Zot (0, 1000, 2000 or 4000ng/ml) were performed using mannitol. The flux of both mannitol and inulin significantly increased (P<0.05) in the presence of Zot. The transport of the enaminones with Zot ranged from 9.42 to 26.83x10(-5)cm/s vs. 4.68 to 13.83x10(-5)cm/s without Zot. Zot significantly increased the transport of all agents tested. This suggests that the co-administration of drugs with Zot may be a useful delivery strategy to increase the intestinal permeability and hence oral absorption of poorly bioavailable agents.
Cox
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DS
Pharmacokinetics Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 100 Penn Street, Baltimore, MD, USA.
Gao
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Raje
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Scott
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Eddington
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ND
D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D018938:Caco-2 Cells / Q000378:metabolism*; D018929:Cell Culture Techniques / Q000379:methods; D002772:Cholera Toxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004234:Diuretics, Osmotic / Q000008:administration & dosage / Q000493:pharmacokinetics; D004731:Endotoxins; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007444:Inulin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008353:Mannitol / Q000008:administration & dosage / Q000493:pharmacokinetics; D008970:Molecular Weight; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*
D000927:Anticonvulsants; D004234:Diuretics, Osmotic; D004731:Endotoxins; C077728:zonula occludens toxin, Vibrio cholerae; D008353:Mannitol; D007444:Inulin; D002772:Cholera Toxin