ISSN:
1573-904X
Keywords:
P-glycoprotein
;
conjunctival transport
;
drug efflux
;
cell culture model
;
propranolol
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. To determine the role of P-glycoprotein (P-gp) in propranololtransport in cultured rabbit conjunctival epithelial cell layers (RCEC). Methods. The localization of P-gp in the cultured RCEC as well asin the excised conjunctiva was determined by immunofluorescencetechnique. The role of P-gp in transepithelial transport and uptake ofpropranolol in conjunctival epithelial cells cultured on Transwell filterswas evaluated in the presence and absence of P-gp competing substrates, ananti-P-gp monoclonal antibody (4E3 mAb), or a metabolicinhibitor, 2, 4-dinitrophenol (2,4-DNP). Results. Immunofluorescence studies revealed positive staining in theapical membrane of cultured RCEC and in the apical surface of thesuperficial cell layers in the excised conjunctiva, but not the basolateralmembrane of cultured RCEC. Transport of propranolol showed preferencein the basolateral-to-apical direction. The net secretory flux wassaturable with a Km of 71.5 ± 24.0 nM and a Jmax of 1.45 ± 0.17pmol/cm2/hr. Cyclosporin A, progesterone, rhodamine 123, verapamil,4E3 mAb and 2,4-DNP all increased apical 50 nM propranolol uptakeby 43% to 66%. On the other hand, neither β-blockers (atenolol,metoprolol, and alprenolol) nor organic cation transporter substrates(tetraethylammonium (TEA) and guanidine), affected apical 50 nMpropranolol uptake. Conclusions. The energy-dependent efflux pump P-gp appears to bepredominantly located on the apical plasma membrane of the conjunctivalepithelium. It may play an important role in restricting the conjunctivalabsorption of some lipophilic drugs.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1007508714259
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