Hypotensive effects and biotransformation of nicorandil, a new antianginal agent, administered to rats by different routes: comparison with nitroglycerin and isosorbide dinitrate

Abstract

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.

Influence of Nicorandil, an Antianginal Agent, on the Therapeutic and Toxic Cardiovascular Actions of Ouabain in the Anaesthetized Dog

“…Unlike conventional nitrates, orally administered nicorandil seems to be more resistant to metabolic breakdown in the liver, and therefore easily enters the systemic circulation. This results in a greater bioavailibility after oral dosing (Sakai et al, 1984). According to a previous experiment (Shiraki et a/., 1981), a bolus intravenous injection of nicorandil (300 pg/kg) in the anaesthetized dog caused a fall of systemic blood pressure over 60 min.…”

Cardioprotective effects of single oral dose of nicorandil before selective percutaneous coronary intervention

“…The plasma concentration of nicorandil decline as mean values of apparent elimination half-life was 52±13 minutes for 20 mg oral doses (42). Investigation about pharmacokinetics of nicorandil proved that nicorandil was rapidly and extensively absorbed from the gastrointestinal tract and no extensive presystemic metabolism seemed to occurred (43, 44). Additionally, IPC was believed to be transient (lasting less than 3 hours) (45).…”

Comparison of the potentiating effects of nicorandil and its denitrated metabolite (SG‐86) on the adenosine‐induced vasodepression in rats

“…Thus, it has been thought that SG-86, a denitrated metabolite of nicorandil, is pharmacologically inactive, and that possesses little interest as the object of precise investigation in this field. However, it should be noted that SG-86 is a main metabolite of nicorandil in humans [6] as well as in animals [16,17,201. Indeed, nicorandil given orally to humans and animals is rapidly absorbed (C,,, 15-30 rnin), and gradually metabolized to SG-86, mainly in the liver.…”

“…N-(2-hydroxyethyl)nicotinamide (SG-86) is a main metabolite of nicorandil [6,16,17,201, which has been reported to be pharmacologically inactive [9,16,17,241. Recently, we found that nicorandil enhances the vasodepressor responses not only to adenosine, but also those to vasoactive intestinal polypeptide and calcitonin gene-related peptide, partly through K ATP channel activation, in rats [ 15, 191.…”