Pharmacokinetic profile of nicorandil in humans: an overview.

Abstract

Nicorandil is rapidly and almost completely absorbed from the gastrointestinal tract. Nicorandil is not metabolized significantly by the liver during passage through the portal system (lack of first-pass effect). Thus, it easily enters the systemic blood flow, resulting in almost complete bioavailability (75-100%). The concomitant food intake decreases the rate of absorption of the drug, resulting in a delay of peak plasma concentration, but has little or no effect on maximal plasma concentration or total amount of absorbed nicorandil. After oral administration of a 5-, 10-, 20-, or 40-mg dose, there is a linear relationship between the doses and increases of maximum plasma concentrations and area under the curve, demonstrating that the pharmacokinetics of nicorandil are linear. Steady-state plasma concentrations of nicorandil usually are reached within approximately 96-120 h after continuous dosing (20 mg b.i.d.), probably due to its distribution and metabolism patterns. On average, the Cmax then is approximately 300 ng/ml, which is achieved rapidly within 30 min after drug intake. Nicorandil is bound weakly to human albumin and other plasma proteins (approximately 25%). After oral (and i.v.) administration of the drug, the apparent volume of distribution is approximately 1.0 L/kg body weight. Nicorandil is metabolized extensively, and the major route of elimination is the kidney: Less than 2% of the dose is excreted through the biliary route. As a consequence, the parent drug is excreted poorly in urine (very low renal clearance), whereas 2-nicotinamidoethanol, a pharmacologically inactive denitrated metabolite, is the major nicorandil-related compound excreted in urine. The nicotinamide/nicotinic acid biotransformation pathway contributes to the accumulation of nicorandil and 2-nicotinamidoethanol (denitrated metabolite) during repeated dosing because of the saturable merging of nicotinamide/nicotinic acid derivatives (from the nicorandil metabolism) into the NAD/NADP endogenous pool of coenzymes. The apparent elimination half-life is short (approximately 1 h), and total body clearance is close to 1.15 L/min, which is lower than the liver blood flow. Especially during repeated dosing, a slower elimination process appears that is related to only approximately 10% of the amount of nicorandil found in plasma. Most of the nicorandil metabolites are excreted during the 24-h period after dosing, with the remainder excreted more slowly (as nicotinamide derivatives). The pharmacokinetics of nicorandil are not altered significantly in elderly persons and in patients who have chronic renal impairment or liver insufficiency. Furthermore, its disposition profile is not modified when concomitant drugs such as drug-metabolizing enzyme inducers or inhibitors are given.(ABSTRACT TRUNCATED AT 400 WORDS)