Systematic studies on the paracellular permeation of model permeants and oligonucleotides in the rat small intestine with chenodeoxycholate as enhancer.
The objective of this study was to mechanistically and quantitatively analyze chenodeoxycholate-enhanced paracellular transport of polar permeants and oligonucleotides in the rat jejunum and ileum. Micellar chenodeoxycholate solutions were used to perturbate the tight junctions. Supporting studies included assessment of the aqueous boundary layer (ABL) with ABL-controlled permeants, measurements of the permeability coefficients and fluxes of the bile acid in dilute and micellar concentrations, and determinations of pore sizes with paracellular probes (urea, mannitol, and raffinose). The paracellular permeability coefficients, P(para), of two model oligonucleotides (ON3 and ON6; 12- and 24-mers with 11 and 23 negative charges, respectively) were determined. The enhanced permeabilities paralleled the increased fluxes of micellar bile salt solutions into mesenteric blood and the opening of the tight junctions as compared to controls. As the pore radius increased from 0.7 nm to a maximum of 2.4 nm in the jejunum and ileum, the absorption of ON3 was enhanced up to sixfold in the jejunum and about 14-fold in the ileum with P(para) values between 0.5 x 10(-6) and 6 x 10(-6) cm/s, whereas ON6 was enhanced up to twofold in the jejunum and fivefold in the ileum with permeabilities between 0.3 x 10(-6) and 2 x 10(-6) cm/s.
Tsutsumi
Keiko
K
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, USA.
Li
S Kevin
SK
Hymas
Richard V
RV
Teng
Ching-Leou
CL
Tillman
Lloyd G
LG
Hardee
Gregory E
GE
Higuchi
William I
WI
Ho
Norman F H
NF
D000465:Algorithms; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002635:Chenodeoxycholic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005079:Excipients; D007082:Ileum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007583:Jejunum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics; D008643:Mesentery / Q000378:metabolism; D009841:Oligonucleotides / Q000493:pharmacokinetics*; D010477:Perfusion; D016062:Porosity; D011887:Raffinose / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000187:drug effects / Q000648:ultrastructure; D014508:Urea / Q000493:pharmacokinetics
D001647:Bile Acids and Salts; D005079:Excipients; D007202:Indicators and Reagents; D009841:Oligonucleotides; D002635:Chenodeoxycholic Acid; D008353:Mannitol; D014508:Urea; D011887:Raffinose