Enhancing the "stickiness" of bile acids to cross-linked polymers: a bioconjugate approach to the design of bile acid sequestrants.
A series of cross-linked polymers have been synthesized by reaction of 2% cross-linked, chloromethylated polystyrene with a tertiary amine derivative (7) of cholic acid (prepared by reaction of cholic acid methyl ester with N,N-dimethyl-ethylenediamine), followed by exhaustive quaternization with trimethylamine. Increased loadings of 7 result in enhanced binding of taurocholate ion and a decrease in its rate of release upon exposure to 50 mM aqueous NaCl. Examination of particle-size effects indicates that film diffusion and particle diffusion both contribute to the observed kinetics. Interruption tests that were carried out confirmed that particle diffusion is kinetically important. The relevance of this bioconjugate approach to the design of bile acid sequestrants for the treatment of hypercholesterolemia is briefly discussed.
Zhang
L h
Lh
Department of Chemistry and Zettlemoyer Center for Surface Studies, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
Janout
V
V
Renner
J L
JL
Uragami
M
M
Regen
S L
SL
D000837:Anion Exchange Resins / Q000138:chemical synthesis* / Q000737:chemistry; D001647:Bile Acids and Salts / Q000737:chemistry*; D002792:Cholestyramine Resin; D002793:Cholic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D003432:Cross-Linking Reagents; D004058:Diffusion; D015195:Drug Design; D007700:Kinetics; D008744:Methylamines / Q000737:chemistry; D010316:Particle Size; D011108:Polymers / Q000737:chemistry*; D012965:Sodium Chloride / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013656:Taurocholic Acid / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
D000837:Anion Exchange Resins; D001647:Bile Acids and Salts; D002793:Cholic Acids; D003432:Cross-Linking Reagents; D008744:Methylamines; C411329:N(2),N(2)-dimethylamino-N(1)-2-ethylcholeamide; D011108:Polymers; D002792:Cholestyramine Resin; D012965:Sodium Chloride; D013656:Taurocholic Acid; C023336:trimethylamine