In vitro intestinal permeability of factor Xa inhibitors: influence of chemical structure on passive transport and susceptibility to efflux.
OBJECTIVE
To study the in vitro intestinal permeability of a number of newly synthesised factor Xa inhibitors to better understand the poor oral absorption of these compounds.


METHODS
The bidirectional transport of the fXa inhibitors was studied in the Caco-2 cell model and isolated rat ileal tissue. An attempt was made to characterize efflux mechanisms with the help of commonly used substrates and inhibitors of various transport proteins. In addition, the transport of the fXa inhibitors was studied in MDCK cells transfected with the human MDR1 gene and expressing large amounts of P-glycoprotein (Pgp).


RESULTS
The in vitro absorptive permeability was low for all but one of the fXa inhibitors. For compounds with non-substituted amidine, a charge (due to ionisation at neutral pH) may have resulted in poor membrane partitioning. Neutral compounds with substituted amidines were effluxed from the epithelial cells. The significance of the secretion process was illustrated by the results obtained for a neutral analogue showing high absorptive Caco-2 cell permeability that was not obviated by efflux. Transport inhibition studies in Caco-2 and permeability studies in the MDR1-transfected MDCK cells consistently showed that Pgp is not involved in the secretion of fXa inhibitors. Besides efflux, metabolic liability limited the permeation of the neutral lipophilic analogues with a carbamate ester.


CONCLUSIONS
Poor intestinal permeability may be an important factor in the incomplete oral absorption of the bisbenzimidazole-type fXa inhibitors. Poor permeability may be related to poor membrane partitioning for hydrophilic analogues, whereas susceptibility to efflux transports and gastro-intestinal enzymatic degradation may limit the permeability of some of the neutral less hydrophilic derivatives.
Schipper
N G
NG
Pharmacia Corporation, Division Biovitrum, Stockholm, Sweden.
Osterberg
T
T
Wrange
U
U
Westberg
C
C
Sokolowski
A
A
Rai
R
R
Young
W
W
Sjöström
B
B
D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002463:Cell Membrane Permeability; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007408:Intestinal Absorption; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents