Pharmacokinetics of nicorandil.

Abstract This report presents the findings of some studies on single intravenous and oral dosing performed in healthy volunteers to determine the pharmacokinetics and preliminary metabolism of nicorandil, a new vasodilator acting via increase of both membrane potassium conductance and intracellular cyclic guanosine monophosphate in vascular smooth muscle. Nicorandil (5 to 40 mg) is rapidly and completely absorbed after oral administration. Absolute bioavailability is 75 ± 23% (mean ± standard deviation) indicating that no significant hepatic first-pass effect exists; peak plasma levels occur within 0.30 to 1.0 hours after dosing. Maximal concentration and area under the plasma concentration time curve of the parent drug are linearly related to a dose range of 5 to 40 mg, which covers the therapeutic regimen proposed for the treatment of patients with angina pectoris. The apparent distribution volume is about 1.4 liters/kg and the plasma concentrations decline according to 2 different processes: (1) a rapid elimination phase (apparent t 1 2β ∼-1 hour) that involves about 96% of the dose found in plasma, and a slower phase between the eighth and twenty-fourth hour that could be the consequence of the vascular affinity of the compound. Nicorandil is weakly bound to human plasma proteins (free fraction greater than 75%) and its mean residence time is close to 1.25 hour. Both in animals and in humans, preliminary metabolic studies show that the main biotransformation pathways are denitration and then introduction into the nicotinamide metabolism. However, unchanged nicorandil and denitrated metabolite excreted into the urine represent only about 1 and 4% of the dose, respectively. The total body clearance of nicorandil is equal to 52 ± 18 liters/hour (about 12 ml/min/ kg) and then lower than the liver blood flow. Finally, it appears that nicorandil exhibits a pharmacokinetic profile that differs from that of conventional organic nitrates and then supports its original mechanism of action. Nevertheless, the complete elucidation of the biodynamics of nicorandil requires further study.