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 micrograms/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 (t1/2) increased with dose. In addition, the approach to apparent steady-state during the infusion phase was not overtly sensitive to the drastic changes in t1/2 observed. 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 described 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 inhibition metabolite. Experimental evidence showed that N-(2-hydroxyethyl) nicotinamide, the major metabolite of nicorandil in rats, and nicotinamide (niacinamide) itself, indeed inhibited nicorandil elimination.
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo 14260.
E L
EL
Bachert
Z W
ZW
Li
L
L
Zhao
S J
SJ
Chung
H L
HL
Fung
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D006207:Half-Life; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020108:Nicorandil; D051381:Rats; D017207:Rats, Sprague-Dawley
D008996:Monoamine Oxidase Inhibitors; D009536:Niacinamide; D020108:Nicorandil