A MODIFIED PRODUCT INHIBITION MODEL DESCRIBES THE NONLINEAR PHARMACOKINETICS OF NICORANDIL IN RATS

Nicorandil, a vasodilator which acts through both cyclic GMP accumulat ion and K+ channel opening, has been used in the treatment of various cardiovascular diseases. We have examined the pharmacokinetics of nico randil 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 mu g/kg/min, n = 3 per dose). Plasma nicor andil concentrations were determined by HPLC. Nicorandil plasma concen trations increased disproportionately with dose, but nicorandil elimin ation obeyed apparent monoexponential kinetics, and the apparent half- life (t(1/2)) increased with dose. In addition, the approach to appare nt steady-state during the infusion phase was not overtly sensitive to the drastic changes in t(1/2) Observed. Pharmacokinetic modelling wit h 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, di d not change the pharmacokinetics of nicorandil, providing experimenta l indication that a cosubstrate depletion model might not be applicabl e. To describe the unique pharmacokinetics, a modified product inhibit ion model was developed. This new model includes the classic competiti ve product inhibition equation, describing both parent and product kin etics, and it incorporates, in addition, separate first-order eliminat ion rate constants for both nicorandil and the inhibiting metabolite. Experimental evidence showed that N-(2-hydroxyethyl) nicotinamide, the major metabolite of nicorandil in rats, and nicotinamide (niacinamide ) itself, indeed inhibited nicorandil elimination.