Investigation of transport mechanism of exendin-4 across Madin Darby canine kidney cell monolayers.
The purpose of this study was to investigate the transport mechanism of exendin-4 using Madin Darby canine kidney (MDCK) cell monolayer as an in vitro model of the human intestinal barrier. The roles of active and passive mechanisms of exendin-4 in the cell models were well studied and the corresponding contributions of the transcelluar and paracellular pathway to exendin-4 transport were also evaluated. Moreover, the apparent permeability coefficient (P(app)) values of exendin-4 were determined in the presence of chitosan, sodium decanoate and ethylenediaminetetraacetic acid (EDTA) to further confirm the relative transport mechanism and to evaluate their potential utility in future formulation design. The results revealed the low transport capacity of exendin-4 (P(app), 0.10±0.06×10(-6) cm/s). And exendin-4 transport across the cell models was time and concentration-dependence, direction and energy-independence, and similar to the passive transport marker. Drug efflux and active transport were not observed. In the presence of absorption enhancers, the P(app) value significantly increased up to 2.2-11.9 folds without apparent cytotoxicity, which is comparable to that of the paracellular transport marker. And the order of enhancement was to the effect of chitosan>EDTA>sodium decanoate, and the order of safety was sodium decanoate≈chitosan>EDTA. These findings demonstrated that exendin-4 transport across MDCK cell monolayer mainly by passive paracellular pathway, which agrees with the result of confocal laser scanning microscopy. And these absorption enhancers can be used as potential safe ingredients to improve oral efficacy of exendin-4.
National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, Changchun, China.
Mengshu
M
Wang
Bingxue
B
Sun
Jiao
J
Feng
Haihong
H
Zhang
Bin
B
Liu
Chun
C
Li
Yan
Y
Chen
Yong
Y
Zhang
Wei
W
Kong
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D048271:Chitosan / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology*; D004285:Dogs; D004492:Edetic Acid / Q000494:pharmacology*; D000077270:Exenatide; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D010539:Permeability; D014688:Venoms / Q000378:metabolism*
D003652:Decanoic Acids; D010455:Peptides; D014688:Venoms; C031071:decanoic acid; D048271:Chitosan; D004492:Edetic Acid; D000077270:Exenatide