A Modified Product Inhibition Model Describes the Nonlinear Pharmacokinetics of Nicorandil in Rats

Nicorandil, a vasodilator which acts through both cyclic GMP accumulation and K⁺ channel opening, has been used in the treatment of various cardiovascular diseases. We have examined the pharmacokinetics of nicorandil in the rat as a function of dose, as both i.v. boluses (9 doses, 0.75 – 12 mg, n = 1-4 per dose), and as a 5-hr infusion followed by a 5-hr washout (6 doses, 10-500 µg/kg/min, n = 3 per dose). Plasma nicorandil concentrations were determined by HPLC. Nicorandil plasma concentrations increased disproportionately with dose, but nicorandil elimination obeyed apparent monoexponential kinetics, and the apparent half-life (t_1/2) increased with dose. In addition, the approach to apparent steady-state during the infusion phase was not overtly sensitive to the drastic changes in t_1/2observed. Pharmacokinetic modelling with several nonlinear models, viz: Michaelis-Menten with parallel first-order, cosubstrate depletion and competitive product inhibition, were carried out. Addition of the sulfhydryl donor, N-acetyl-L-cysteine, did not change the pharmacokinetics of nicorandil, providing experimental indication that a cosubstrate depletion model might not be applicable. To describe the unique pharmacokinetics, a modified product inhibition model was developed. This new model includes the classic competitive product inhibition equation, describing both parent and product kinetics, and it incorporates, in addition, separate first-order elimination rate constants for both nicorandil and the inhibiting metabolite. Experimental evidence showed that N-(2-hydroxyethyl) nico-tinamide, the major metabolite of nicorandil in rats, and nicotinamide (niacinamide) itself, indeed inhibited nicorandil elimination.