Hypotensive effects and biotransformation of nicorandil, a new antianginal agent, administered to rats by different routes: comparison with nitroglycerin and isosorbide dinitrate.
The effects of nicorandil, N-(2-hydroxyethyl)nicotinamide nitrate (ester), in reducing systemic blood pressure (SBP) in rats were studied in comparison with isosorbide dinitrate and nitroglycerin. The drugs were administered to pentobarbitone-anaesthetized rats by jugular vein (i.v.), portal vein (p.v.), intrajejunal (i.j.), intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Nicorandil was absorbed rapidly through all routes, and caused marked hypotension dose-dependently. With isosorbide dinitrate and nitroglycerin, unlike nicorandil, the p.v. dose required to induce a vasodepressor response was significantly greater than that required to cause a comparable response after i.v. administration. In non-recirculating rat liver perfusion experiments, nicorandil was reduced only 5-10% during a single passage through the liver, while nitroglycerin was reduced over 95%. In recirculating liver perfusion experiments, the progressive decrease of nicorandil in the blood recirculated was accompanied by a corresponding increase of SG-86, a dinitrate compound of nicorandil (its main metabolite). Sixty min after dosing, nicorandil was decreased by approximately 73% of the initial nicorandil blood concentration and SG-86 was increased by approximately 70%. The extent of degradation of nicorandil in liver homogenates, examined by thin-layer chromatography, was in the following order: rat = guinea-pig greater than dog = monkey greater than pig. In these species a close inverse relationship is apparent between the rate of liver nicorandil degradation and hypotensive effects of nicorandil.
D000818:Animals; D000959:Antihypertensive Agents; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D020108:Nicorandil; D005996:Nitroglycerin / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate