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DMP 504, a novel hydrogel bile acid sequestrant: I. equilibrium binding properties and computer simulation of human bile flow
Author(s) -
Shimshick Edward J.,
Figuly Garret D.,
Grimminger Lisa C.,
Hainer James W.,
Jensen James H.,
Leipold Robert J.,
Royce Susan D.,
Gillies Peter J.
Publication year - 1997
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199706)41:2<58::aid-ddr2>3.0.co;2-q
Subject(s) - bile acid , taurine , cholestyramine , chemistry , chromatography , cholesterol , biochemistry , amino acid
DMP 504 is a novel bile acid sequestrant under development for the treatment of primary hypercholesterolemia. The resin is a soft‐textured “hydrogel” that is synthesized from 1,10‐dibromodecane and 1,6‐diaminohexane. The equilibrium binding parameters for DMP 504 have been determined and compared to cholestyramine (CS) with respect to the major trihydroxy bile acid, glycocholate (GC), and the major dihydroxy bile acid, glycochenodeoxycholate (GCDC). DMP 504 had a greater maximum binding capacity (Bmax) than CS for GC (5.47 ± 0.06 vs. 2.76 ± 0.17 moles/kg) and GCDC (5.71 ± 0.14 vs. 3.26 ± 0.11 moles/kg). DMP 504 had a greater affinity, i.e., a lower Kd, than CS for GC (1.78 ± 0.04 vs. 5.24 ± 0.64 mM) and GCDC (0.19 ± 0.01 vs. 0.52 ± 0.06 mM). Similar values were obtained for the taurine conjugates of cholate and chenodeoxycholate. Since the interaction of bile acids with DMP 504 was highly cooperative, the binding isotherms were analyzed with a model that included a cooperativity parameter (W) to allow for interactions between adjacently bound bile acids. The DMP 504 binding isotherms showed greater cooperativity than CS for GC (5.10 ± 0.42 vs. 1.81 ± 0.47) and GCDC (6.28 ± 1.68 vs. 2.40 ± 0.76). A mathematical model of human bile flow, using the values for Bmax, Kd, and W determined in this study predicted that DMP 504 would be approximately threefold more potent than CS in a clinical setting. Drug Dev. Res. 41:58–64, 1997. © 1997 Wiley‐Liss, Inc.