The effect of the mode of administration on the hypolipidaemic activity of niacin: continuous gastrointestinal administration of low-dose niacin improves lipid-lowering efficacy in experimentally-induced hyperlipidaemic rats.

The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia-Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg(-1)). Continuous administration of niacin into the duodenum at 1.66 mg h(-1) (total dose 40 mg kg(-1) day(-1)) for up to 7 days (Model A) or at 2.22 mg h(-1) over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15-25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg(-1)) has a greater lipid-lowering effect than a higher dose (200 mg kg(-1)) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.