Directional Transcellular Transport of Bisoprolol in P-glycoprotein-expressed LLC-GA5-COL150 Cells but not in Renal Epithelial LLC-PK1 Cells

To evaluate the mechanism responsible for the tubular secretion of bisoprolol, we compared transcellular transport of bisoprolol with that of tetraethylammonium (TEA), cimetidine, and quinidine across LLC-PK1 cell monolayers grown on porous membrane filters. TEA and cimetidine were actively transpor...

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Published in:Drug metabolism and pharmacokinetics 2008-01, Vol.23 (5), p.340-346
Main Authors: Tahara, Katsutoshi, Kagawa, Yuka, Takaai, Mari, Taguchi, Masato, Hashimoto, Yukiya
Format: Article
Language:English
Subjects:
Animals
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
bisoprolol
Bisoprolol - pharmacokinetics
cationic drugs
Cells, Cultured
Cimetidine - pharmacokinetics
kidney epithelial cell line
kinetic analysis
LLC-PK1 Cells
Organic Cation Transport Proteins - metabolism
Quinidine - pharmacokinetics
renal secretion
Swine
Tetraethylammonium - pharmacokinetics
transcellular transport
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Summary:To evaluate the mechanism responsible for the tubular secretion of bisoprolol, we compared transcellular transport of bisoprolol with that of tetraethylammonium (TEA), cimetidine, and quinidine across LLC-PK1 cell monolayers grown on porous membrane filters. TEA and cimetidine were actively transported in the basolateral-to-apical direction by the specific transport system. Pharmacokinetic analysis indicated that basolateral influx and apical efflux were cooperatively responsible for the directional transport of TEA and cimetidine. Lipophilic cationic drugs, quinidine, S-nicotine, and bisoprolol, significantly diminished basolateral influx and apical efflux clearance of cimetidine. However, transcellular transport of quinidine in the basolateral-to-apical direction was similar to that in the opposite direction in LLC-PK1 cells. In contrast, quinidine was transported actively in the basolateral-to-apical direction in P-glycoprotein-expressed LLC-GA5-COL150 cells. Pharmacokinetic analysis indicated that P-glycoprotein increased the apical efflux of quinidine and also decreased the apical influx of the drug. Basolateral-to-apical transport of bisoprolol was also similar to apical-to-basolateral transport in LLC-PK1 cells, whereas the drug was directionally transported from the basolateral to the apical side in LLC-GA5-COL150 cells. These results suggested that bisoprolol was not significantly transported via transport systems involved in the directional transport of TEA and cimetidine, but that P-glycoprotein was responsible for the directional transport of bisoprolol as well as quinidine in renal epithelial cells.
ISSN:1347-4367
1880-0920
DOI:10.2133/dmpk.23.340