DMP-504, A NOVEL HYDROGEL BILE-ACID SEQUESTRANT - II - LIPID-LOWERINGPHARMACOLOGY IN THE HAMSTER

DMP 504 is a novel hydrogel bile acid sequestrant in development for t he treatment of moderate hypercholesterolemia. The drug is a condensat ion polymer synthesized from 1,10-dibromodecane and 1,6-diaminohexane. In vitro binding studies demonstrate that DMP 504 is superior to chol estyramine (CS) with respect to equilibrium binding capacity and affin ity for bile acids. The goals of the research reported herein were to assess the in vivo hypolipidemic activity of DMP 504, to elucidate the mechanism of action of DMP 504, and to determine the potency of DMP 5 04 relative to CS in hamsters. Six dose groups each of DMP 504 and CS were included in the study, along with an untreated control group. The DMP 504 doses ranged from 20-1,000 mg/kg/day for 14 days; CS doses ra nged from 50-2,000 mg/kg/day for 14 days. There were 48 animals per do se group; drugs were administered in the feed. At the midpoints of the dose-response curves, DMP 504 was superior to CS with respect to incr easing the output of fecal bile acids (7-fold) and sterols (3-fold), i ncreasing the activity of hepatic cholesterol 7 alpha-hydroxylase acti vity (6-fold) (6-fold), and decreasing the circulating levels of total serum cholesterol (6-fold), non-HDL cholesterol (6-fold), and HDL cho lesterol (4-fold). Neither DMP 504 nor CS had significant effects on s erum triglycerides or apo-B. In summary, DMP 504 is a new bile acid se questrant that is mechanistically similar to CS, but is, on average, 6 -fold more potent. (C) 1997 Wiley-Liss, Inc.