Pharmacodynamic effects of bezafibrate and niacin combination: Implications of the mode of administration

The goal of this investigation was to optimize antilipid therapy by utilizi ng the combined activity of two lipid-lowering agents, niacin and bezafibra te, and improve their efficacy by targeting them to their presumed presyste mic site(s) of action. Thus, continuous duodenal (IGI) administration of th e drug combination should augment their efficacy in comparison with intermi ttent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on o n acute hyperlipidemia induced by triton injection. Continuous IGI administ ration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg /kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced signifi cantly greater lowering of total cholesterol and triglycerides and elevatio n of high-density lipoprotein (HDL) cholesterol in comparison with intermit tent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafi brate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix ta blet of the drug combination resulted in a similar magnitude of effect as t he IGI administration, the present study provides a pharmacodynamic rationa le for the use of a slow-release low-dose niacin-bezafibrate combination. ( C) 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association.