Bile acid binding to sevelamer HCl.
BACKGROUND
Clinical studies have shown sevelamer HCl (Renagel) to be effective for the reduction of serum phosphate in hemodialysis patients. These studies also consistently have demonstrated a significant reduction of low-density lipoprotein (LDL) cholesterol following treatment with sevelamer.


METHODS
Equilibrium binding of bile acids and oleic acid was determined by incubating sevelamer with ligand containing buffer. Aliquots of the solution were filtered and the free ligand concentrations quantitated by high-pressure liquid chromatography (HPLC). Flow kinetics were determined using a cylindrical flow cell containing trapped sevelamer. Bile acid and oleic acid were pumped through the stirred cell in a manner designed to mimic the in vivo situation. Binding was monitored by HPLC.


RESULTS
Sevelamer binds bile acids cooperatively and with high capacity. At low binding densities, the presence of the more hydrophobic bile acids enhances the binding of the less hydrophobic bile acids, and the presence of oleic acid enhances the binding of all bile acids. At saturating oleic acid concentrations, the bile acid binding capacity of sevelamer is reduced by only a factor of two. Moreover, the presence of oleic acid dramatically diminishes the release rate of bile acids from sevelamer.


CONCLUSIONS
The favorable bile acid binding characteristics of sevelamer provide a compelling explanation for its ability to lower LDL cholesterol in hemodialysis patients and in healthy volunteers.
Braunlin
William
W
GelTex Pharmaceuticals, Waltham, Massachusetts, USA. william.braunlin@verizon.net
Zhorov
Eugene
E
Guo
Amy
A
Apruzzese
William
W
Xu
Qiuwei
Q
Hook
Patrick
P
Smisek
David L
DL
Mandeville
W Harry
WH
Holmes-Farley
S Randall
SR
D001647:Bile Acids and Salts / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy; D007700:Kinetics; D008954:Models, Biological; D019301:Oleic Acid / Q000378:metabolism / Q000494:pharmacology; D011073:Polyamines; D011095:Polyethylenes / Q000378:metabolism* / Q000494:pharmacology*; D006435:Renal Dialysis; D000069603:Sevelamer
D001647:Bile Acids and Salts; D008078:Cholesterol, LDL; D004852:Epoxy Compounds; D011073:Polyamines; D011095:Polyethylenes; D019301:Oleic Acid; D000069603:Sevelamer